The Role of Geographical Ecological Studies in Identifying Diseases Linked to UVB Exposure and/or Vitamin D
William B. Grant Ph.D.a*
Received: 22 Dec 2015, Accepted: 28 Dec 2015, Accepted author version posted online: 08 Jan 2016
Using a variety of approaches, researchers have studied the health effects of solar ultraviolet (UV) radiation exposure and vitamin D. This review compares the contributions from geographical ecological studies with those of observational studies and clinical trials. Health outcomes discussed were based on the author's knowledge and include anaphylaxis/food allergy, atopic dermatitis and eczema, attention deficit hyperactivity disorder, autism, back pain, cancer, dental caries, diabetes mellitus type 1, hypertension, inflammatory bowel disease, lupus, mononucleosis, multiple sclerosis, Parkinson's disease, pneumonia, rheumatoid arthritis, and sepsis. Important interactions have taken place between study types; sometimes ecological studies were the first to report an inverse correlation between solar UVB doses and health outcomes such as for cancer, leading to both observational studies and clinical trials. In other cases, ecological studies added to the knowledge base. Many ecological studies include other important risk-modifying factors, thereby minimizing the chance of reporting the wrong link. Laboratory studies of mechanisms generally support the role of vitamin D in the outcomes discussed. Indications exist that for some outcomes, UVB effects may be independent of vitamin D. This paper discusses the concept of the ecological fallacy, noting that it applies to all epidemiological studies.
- Sun and UV
- Opinion: sun better than UV better than vitamin D by Henry Lahore
- IBD more likely in areas with low UV ( and thus low vitamin D) – June 2014
- A review of the evidence regarding the solar ultraviolet-B-vitamin D-cancer hypothesis - Oct 2012 Grant
- 2200X more problem from no UVB than too much UVB - WHO 2006
and - list of health problems at the bottom of this page
Table of contents
- 1. Introduction
- 2. Methods and Data
- 3. Results
- 3.1.a. Dental Caries
- 3.1.b. Mononucleosis
- 3.1.c. Pneumonia
- 3.1.d. Respiratory Syncytial Virus
- 3.1.e. Sepsis
- 3.2.a. Cancers with Increased Risk from UV Exposure
- 3.2. b. Cancer with UVB as a Risk-Reduction Factor
- Table 1 Key papers supporting beneficial roles of UVB and/or vitamin D in reducing risk of cancer
- Table 2 Key papers reporting null or adverse effects of UVB and/or vitamin D on cancer incidence
- 3.3.a. Diabetes Mellitus Type 1
- 3.3.b. Inflammatory Bowel Disease: Crohn's Disease and Ulcerative Colitis
- 3.3.c. Lupus Erythematosus, Cutaneous and Systemic
- 3.3.d. Multiple Sclerosis
- 3.3.e. Rheumatoid Arthritis
- 3.4.a. Anaphylaxis/Food Allergy
- 3.4.b. Atopic Dermatitis and Eczema
- 3.4.c. Attention Deficit Hyperactivity Disorder
- 3.4.d. Autism
- 3.4.e. Lower Back Pain
- 3.4.f. Hypertension
- 3.4.g. Parkinson's Disease
- 3.4.h. Rickets
- Table 3 Pioneering studies regarding ecological and observational studies and clinical trials for diseases reviewed in this paper.
- 3.21. Ecological Fallacy
- 4. Discussion
- 5. Conclusion
- See Health Problems in VitaminDWiki
By now a large body of journal literature describes the health benefits of ultraviolet-B (UVB) exposure and vitamin D. The classical role of vitamin D is to help regulate calcium absorption and metabolism. Rickets was the first disease linked to inadequate sun exposure and vitamin D, with highest rates in the early 20thcentury among those living in crowded and polluted cities where people had little sun exposure 1. This paper reviews the history of discovery of the role of UVB exposure and/or vitamin D in health outcomes for which geographical ecological studies have been reported, especially those in which such studies played an important role in understanding the role of vitamin D. The goal is to examine the relative contributions of all types of studies in establishing the links as well as to assess the current understanding of the robustness of the links. The motivation is to see whether geographical ecological studies should be given more credit than is generally the case.
Four methods exist to determine whether UVB exposure and vitamin D affect disease outcomes: ecological studies, observational studies, laboratory studies, and clinical trials.
Ecological studies can be of two types:
• Geographical. Health outcomes and risk-modifying factors are averaged for populations divided along geographical lines.
• Temporal. Health outcomes are examined for seasonal variations or trends.
Observational studies come in several forms:
• Case–control. Risk-modifying factors measured at the time of disease diagnosis.
• Cohort and nested case–control. Subjects are enrolled in a study, risk-modifying factors are assessed, and then the cohort is monitored (for up to many years). Those who develop diseases are compared with like individuals who did not.
• Cross-sectional. An entire population is sampled, with health status and health parameters and risk-modifying factors measured.
Laboratory studies are generally of three types:
• Animal studies. Animal models of various diseases are challenged with various agents.
• Detailed cell and tissue analysis. Cells and tissues from patients can be examined for genetic variations, etc.
In clinical trials, people are enrolled and randomly assigned to take a substance or a placebo for a specified time. The object is to see whether taking the agent yields a better result for the outcome of interest.
Health policy is generally based on clinical trials; however, observational study results are used if, for example, clinical trial results are not available—perhaps due to ethical concerns, such as was the case for linking smoking to lung cancer and other diseases 2.
Ecological studies have played important roles in understanding how diet affects risk of disease. A 1975 multicountry ecological study linked dietary factors to cancer incidence rates in 23 countries and mortality rates in 32 countries 3. Meat and animal protein generally had the highest correlation with many cancers common in Western developed countries. This finding was preceded by similar findings such as a study of cancer rates in ethnic groups living in or near Chicago in the early 1900s. People from countries that ate large amounts of meat had high cancer rates, whereas people from countries such as Italy, where people favored pasta, or China, where people ate rice, had low rates of cancer 4. However, it took many years before the findings of the 1975 study were generally accepted since observational studies involving older people did not confirm the findings. However, researchers eventually realized that diet's effect might be more strongly linked to diet in early life. Therefore, when younger women were used in a study of diet and breast cancer, meat was considered an important risk factor 5. Observational studies in Uruguay offers strong support for meat as an important risk factor for many cancers 6. A recent multi-country study involving 157 countries generally confirmed the findings of the 1975 study and added some other factors such as smoking and per capita gross domestic product 7.
Another example of the value of ecological studies is for Alzheimer's disease (AD). The first study linking diet to risk of AD was an ecological one. That study strongly correlated total fat and total energy supply with risk, with fish and cereals/grains inversely correlated 8. Those results led to observational studies that confirmed the basic findings 9, 10. More recently, I used the ecologic study approach to link the dramatic rise in AD rates in Japan to the nutrition transition from the traditional Japanese diet to the Western diet with a lag of about 25 years 11. Also, national diets with a greater proportion of foods cooked at high temperature such that they have high levels of advanced glycation end products 12 also correlate with AD rates 13. Two recent reviews underscored the importance of diet in affecting risk of AD 14, 15.
This is a narrative review, with papers chosen to show how different study types ascertain the role of UVB exposure and vitamin D in reducing risk of adverse health outcomes. The papers cited here were generally found by searching the National Library of Medicine's PubMed database (pubmed.gov) with terms including the name of the condition or disease along with geographical, latitude, vitamin D, 25-hydroxyvitamin D, ecologic, ecological, and mechanisms.
An account of a latitudinal gradient in missing teeth was reported for those exempted from service in the Union Army during the Civil War, with much higher rates in northern states 16. It was first demonstrated that vitamin D could reduce the risk of dental caries in the 1920. Mellanby and Pattison reviewed their work on dietary vitamin D and vitamin D2 supplementation on reducing development and spread of dental caries 17. They attributed the beneficial effects of vitamin D to higher calcium content of the teeth, but they noted that in the arrested dental caries, the microorganisms appeared “inactive.” Vitamin D's role in killing bacteria had, of course, not been identified then, but as good scientists they reported what they saw. Only recently was it realized that vitamin D induced production of cathelicidin, which has antibiotic properties and plays an important role in killing bacteria that cause dental caries 18. Several ecological studies reported on the relation between dental caries and solar UVB doses in the 1930s (e.g., 19) and in Oregon in the 1950s (e.g., 20), reviewed in 18. One paper reported dental rank by state for dental disease (higher rank for greater incidence of dental disease) for three groups of U.S. servicemen from 1918 to 1943 21. A scatter plot of average rank versus solar UVB doses for July 1992 showed a rapid decrease in rank from solar UVB doses of 3.5 to 7.0 kJ/m2 followed by little change thereafter 18. In the 1920s–1940s, controlled clinical trials of vitamin D to reduce dental caries took place; those studies showed significant beneficial results 22. Unfortunately, modern dentistry has forgotten these studies.
Risk of infectious mononucleosis (IM) has long been known to be linked to that of multiple sclerosis (MS) 23, 24. A study in England found that the geographical variation of hospital admissions for IM was similar to that for MS 25. In addition, incidence of IM was highest in spring in Italy and Norway 26. Epstein–Barr virus is a risk factor for IM 27. Vitamin D is very likely to reduce risk of Epstein–Barr virus diseases 28.
A 1997 paper proposed that pneumonia incidence among children with rickets in Ethiopia was due to low 25(OH)D concentrations 29. An ecological study found that solar UVB doses from either summertime or wintertime reduced the fatality rate of influenza during the 1918–1919 pandemic influenza in the U.S. 30. The mechanisms proposed were that vitamin D induced production of cathelicidin, which has antibiotic properties, and that vitamin D reduced the cytokine storm associated with influenza, thereby reducing damage to the epithelial layer of the lung and reducing risk of bacterial infection. Vitamin D reduces risk of community-acquired pneumonia 31. However, 1,25-dihydroxyvitamin D [1,25(OH)2D] is the important metabolite of vitamin D in combating community-acquired pneumonia, and some people cannot convert 25(OH)D to 1,25(OH)2D efficiently 32.
A study of weekly incidence of respiratory syncytial virus (RSV) with respect to meteorological conditions found that a 13% reduction in incidence rates could be attributed to UVB doses in Miami, 5% in Buffalo, and 0.5% in Winnipeg, Manitoba 33. A laboratory study using RSV-infected epithelial cells found that vitamin D decreases the inflammatory response to viral infections in airway epithelium by reducing production of proinflammatory cytokines and chemokines 34. Cord blood 25(OH)D deficiency was associated with RSV bronchiolitis 35.
Cathelicidin, which has antibiotic and antiendotoxin effects and is induced by 1,25(OH)2D 36, has been called an antisepsis molecule 37. A paper reporting that the seasonal chance of sepsis was highest in the northeastern U.S. 38 was the inspiration for the UVB–vitamin D–sepsis hypothesis 39. Additional evidence cited included higher rates for black Americans than white Americans, comorbid diseases linked to low 25(OH)D concentrations, and higher rates in urban than in rural regions. A study in Georgia found directly correlated concentrations of cathelicidin with 25(OH)D concentrations for people with sepsis 40. Low 25(OH)D concentration is now considered causally linked to risk of sepsis 41. A study in Boston associated 25(OH)D concentrations <25 nmol/L with a multifactor adjusted odds ratio of 1.95 (95% CI =1.22–3.12) for hospital-acquired bloodstream infection 42. A study in Utah found that having 25(OH)D concentration <37 nmol/L was associated with an odds ratio of 1.89 (95% CI = 1.09–3.31) of developing sepsis 43. Similar results were found in Graz, Austria 44.
Researchers generally consider UV exposure to be the primary risk factor for melanoma and nonmelanoma skin cancer (basal cell carcinoma and squamous cell carcinoma). Because conducting trials on humans with UV radiation to see whether they develop skin cancer would be unethical, researchers must use other types of studies—in general, observational studies and ecological studies. Ecological studies have several advantages over observational studies. Those advantages include involving more cases and the use of UV exposure indices that are generally more reliable than those of personal recall. However, occupational exposure to UV is also a good measure.
The first ecological study linking skin cancer to latitude in the U.S. was based on data collected from 10 large metropolitan areas in 1937–1938 45. The study was repeated, using data from 1947–1948 46. In that study, age-adjusted skin cancer incidence rates varied from 130 cases/100,000people/yr for females and 190/100,000/yr for males in Birmingham (33.3° N) to 22/100,000/yr for females and 30/100,000/yr for males in Chicago (41.9° N). Skin cancer rates have been inversely correlated with latitude in Chile 47. Nonmelanoma skin cancer incidence rates were directly correlated with long-term mean daily sunshine hours but not with environmental arsenic or mean household radon levels 48.
One interesting use of the ecological approach regarding skin cancer was to investigate in various countries how latitude varied among light-skinned people. From the slope of incidence and mortality rates, that study deduced that UVA radiation is more important for melanoma, whereas UVB is clinically more important for basal cell carcinoma and squamous cell carcinoma 49.
A 1988 ecological study linked salivary gland cancer to UV exposure 50. Those same authors extended the link to lip cancer by comparing incidence of lip cancer and melanoma for people diagnosed with salivary gland cancer 51.
An occupational study in Sweden found increased risk of myeloid leukemia (relative risk [RR] = 2.0, 95% confidence interval [95% CI] = 1.1–3.6) and lymphocytic leukemia (RR = 1.7, 95% CI = 0.9–3.2) in the high–UV exposure group; the risk of non-Hodgkin's lymphoma increased nonsignificantly (RR = 1.3, 95% CI = 0.9–1.9) 52. Recently I proposed that UVA may increase the risk of lymphoma by impairing the immune system response, whereas UVB reduces risk; in high-latitude countries the UVA to UVB ratio is higher than that in low-latitude countries 53.
Both cervical and pharyngeal cancer rates were directly correlated with UV doses for white people in the United States 54. Both cancers are linked to human papillomavirus. An observational study involved >900,000 consecutive, serially independent, interpretable screening Pap smears obtained by a single cervical cancer screening laboratory in Leiden, Holland, over 16 years from 1983 through 1998. Human papillomavirus activity peaked in August 55. Those authors later attributed the finding to reduced immune function due to UV exposure 56.
Several ecological studies have assessed cancer incidence and/or mortality rates with respect to indices of solar UVB doses. Studies in single midlatitude countries have yielded the best results, in part since the populations are relatively homogeneous or, if not, the variations in ethnic background can be modeled as in the U.S. 57. Ecological studies reporting inverse correlations between incidence and/or mortality rates for several types of cancer with respect to indices of solar UVB doses, generally with other risk-modifying factors included in the analysis, have been reported for Australia 58, 59, China 60, France 61, Spain 62, and the U.S. 57, 63, 64. In addition, a study based on UV exposure by occupation found inverse correlations with the UVB index (lip cancer less lung cancer) for 14 cancers for males and four for females 65.
Ecological studies of cancer incidence and/or mortality rates with respect to geographical variations in solar UVB doses have been crucial to understanding how UVB exposure and vitamin D affect risk for and survival of many cancers. For example, Garland and Garland's 1980 ecological study of colon cancer and annual sunlight 66 led to their dietary vitamin D study in 1985 67 and their serum 25(OH)D concentration study in 1989 68. One test of a good scientific hypothesis is whether predictions based on it prove correct, and the three papers by the Garland brothers and colleagues serve as an example of prediction and confirmation. In addition, the ecological study extending the UVB–vitamin D–cancer hypothesis to 15 cancers 63 led to an observational study that used “predicted vitamin D” in the Health Professionals Follow-Up Study 69 and analysis of a clinical trial originally designed to study the effect of vitamin D and calcium on risk of osteoporosis 70. A meta-analysis shows that breast cancer incidence rates are reduced for higher 25(OH)D concentrations as long as follow-up time is considered 71. For colorectal cancer, a gradual reduction in the effect occurs with increasing follow-up time, whereas for breast cancer, most studies with follow-up times longer than 3 years do not find significant inverse correlations with respect to 25(OH)D concentration. The dichotomy is explained in terms of the much more rapid progression of breast cancer to the point of being detectable. Few other cancers exist for which observational studies based on 25(OH)D concentrations found significant inverse correlations; bladder cancer is one such example 72. Cancer survival rates are higher for higher 25(OH)D concentrations at time of diagnosis for breast cancer, colorectal cancer, lung cancer, and lymphoma 73, 74.
The mechanisms whereby vitamin D reduces risk of cancer and increases survival are largely known and include effects on cellular differentiation, proliferation and apoptosis, angiogenesis, metastasis, and inflammation 75, 76.
Some reports find higher risk of cancer at higher 25(OH)D concentrations. The most notable example is prostate cancer, for which a U-shaped relation with 25(OH)D concentration was first reported in 2004 77. Pancreatic cancer, with direct correlations at high latitudes 78, 79, is another example. The U-shaped 25(OH)D concentration–prostate cancer incidence relation has been confirmed in many studies since 2004 80 as well as a direct correlation with UVB dose in a study in a high–UVB dose region of Australia 81. Although the first suggestion that UVB reduced the risk of prostate cancer mortality came from an ecological study 82, a more recent investigation found that the geographical variation of prostate cancer mortality rate in the U.S. 83 is linked primarily to life expectancy, with rates directly correlated with life expectancy 84. As for pancreatic cancer, analysis of results from two U.S. cohort studies shows that pancreatic cancer incidence rate is inversely correlated with 25(OH)D concentration 85. Also, ecological studies show inverse correlations between solar UVB doses and pancreatic cancer rates 76. The likely explanation for the finding of a direct correlation between 25(OH)D concentration and incidence of pancreatic cancer at higher latitudes is that since UVB doses are low, some people started taking vitamin D supplements shortly before enrolling in the study. Support for this hypothesis comes from two studies of frailty with respect to 25(OH)D concentration in the U.S.: for women, the relation is U-shaped 86, whereas for men an inverse relation occurs 87. Elderly women in the U.S. are much more likely to be advised to take vitamin D supplements than are elderly men. In addition, an analysis of 3.8 million laboratory analyses of 25(OH)D concentration in the U.S. found that for those with 25(OH)Dtotal >125 nmol/L, the percentages with 25(OH)D2 >10 nmol/L were 76% in the north, 15% in the center, and 9% in the south 88.
Some disagreement persists over whether vitamin D reduces risk of diseases in general and cancer in particular. The primary reason stated is that clinical trials offer little support for observational studies 89,90,91,92,93. Such findings led some to suggest that low 25(OH)D concentration is a result of poor health, rather than a cause of it 89. The primary reason that clinical trials do not provide much support seems to be that they have not been properly designed. Heaney recently outlined guidelines for nutritional trials that apply to vitamin D trials 94. The key points are as follows:
- 1.Start with an understanding of the 25(OH)D concentration–health outcome relation.
- 2.Measure 25(OH)D concentration for prospective participants.
- 3.Enroll only those with concentrations near the low end of the relation.
- 4.Supplement with enough vitamin D3 to raise concentrations to the upper region.
- 5.Remeasure 25(OH)D concentrations.
- 6.Make sure that conutrient status is optimized.
A recent review concluded that clinical trials with baseline 25(OH)D concentration <48 nmol/L had a 50% chance of finding a significant reduction in biomarkers of inflammation but that trials with baseline 25(OH)D concentration >50 nmol/L had only a 26% chance 95. In fact, one vitamin D-plus-calcium clinical trial did show significant reductions in breast and all-cancer incidence rates and nonsignificant reductions in colorectal cancer incidence for people who had not taken vitamin D or calcium supplements before entering the study 96.
Another way to assess the strength of the UVB–vitamin D–cancer hypothesis is to use results of geographical ecological studies. Ecological studies in midlatitude countries and an occupational study in Nordic countries find significant inverse correlations between indices of solar UVB doses or exposure and cancer incidence and/or mortality rates for 15–20 types of cancer, often after considering other cancer risk–modifying factors. Therefore, it has to be concluded that UVB exposure reduces the risk of many cancers. UVB exposure is the most important source of vitamin D, which has many cancer-reducing mechanisms 76. An alternative hypothesis would be that UVB reduces cancer risk through non–vitamin D mechanisms. One animal study found that such mechanisms related to cancer progression might exist, but not those related to cancer incidence 97. Thus, the UVB–cancer hypothesis does not work without vitamin D.
Table 1 lists key papers supporting beneficial roles of UVB and/or vitamin D, and risk of cancer in historical order. Ecological studies have played key roles since 1941.
|Year||Type of study||Finding||Reference|
|1937||Observational||“Skin irritation” associated with reduced risk of internal cancers||98|
|1941||Ecological||Inverse correlation of cancer with respect to solar radiation||99|
|1980||Ecological||Colon cancer morality rate inversely correlated with annual solar radiation; vitamin D suggested as mechanism||66|
|1981||Laboratory||Differentiation of mouse leukemia cells induced by 1,25-dihydroxyvitamin D||100|
|1981||Laboratory||1,25-dihydroxivitamin D interacted with vitamin D receptors to reduce melanoma cell growth||101|
|1985||Observational||Dietary vitamin D and calcium associated with reduced risk of colon cancer||67|
|1985||Ecological||Direct correlation of latitude with pancreatic cancer mortality rates in Japan||102|
|1989||Observational||Colon cancer incidence inversely correlated with 25(OH)D concentration in the U.S.||68|
|1990||Ecological||Breast cancer mortality rate inversely correlated with solar radiation in the U.S.||103|
|1992||Ecological||Prostate cancer mortality rate found inversely correlated with prostate cancer mortality rate in the U.S.||104|
|2002||Ecological||15 cancers in the U.S. inversely correlated with July UVB doses||63|
|2004||Observational||U-shaped 25(OH)D-prostate cancer incidence relation found||77|
|2006||Ecological||15 cancers in the U.S. inversely correlated with July UVB doses; other risk-modifying factors included||57|
|2006||Observational||Many cancers inversely correlated with “predicted 25(OH)D concentration”||69|
|2007||Clinical trial||All-cancer incidence rates significantly reduced with 1100 IU/d of vitamin D3 and 1500 mg/d of calcium||70|
|2011||Clinical trial||In women who were not taking personal calcium or vitamin D supplements at randomization, taking calcium plus vitamin D significantly decreased the risk of total, breast, and invasive breast cancers by 14%–20% and nonsignificantly reduced the risk of colorectal cancer by 17%||96|
|2012||Observational||Better survival rates for cancers of the breast, colon, lung, and lymphoma for higher 25(OH)D concentration at time of diagnosis||73|
|2012||Ecological?||Outdoor occupation inversely correlated with 15 cancers in Nordic countries||65|
|2013||Ecological||Review of single-country ecological mechanisms||76|
|2015||Observational||Meta-analyses of breast and colorectal cancer with respect to 25(OH)D concentration and follow-up time||105|
There are, of course, a number of studies that reported null or adverse effects of UVB exposure, vitamin D intake, or 25(OH)D concentrations on cancer incidence. A few such key papers are listed in Table 2 along with suggested reasons why they failed to find a beneficial effect.
|Year||Type of Study||Finding||Reference||Reason||Reference|
|2006||Observational||Direct correlation between 25(OH)D concentration and incidence of pancreatic cancer||78||Likely that those with the highest 25(OH)D concentrations had only recently begun supplementing with vitamin D|
|2006||Randomized controlled trial||No effect of 400 IU/d vitamin D3 plus 1500 mg/d calcium on risk of colorectal cancer||106||Too little vitamin D3 for those already taking vitamin D or calcium prior to enrolling in study||96|
|2009||Observational||Direct correlation between 25(OH)D concentration and incidence of pancreatic cancer at higher U.S. latitudes||79||Those with high 25OHD concentrations had only begun supplementation with vitamin D shortly before entering the study||88|
|2010||Observational||No inverse correlation between 25(OH)D concentration and incidence of rarer types of cancer||107||Long (˜9 year follow up); too few cases at higher 25(OH)D concentrations||108|
|2011||Observational||Direct correlation of 25(OH)D concentration with incidence of colon cancer||109||At odds with nearly all other studies on colon cancer; possibly due to long follow-up time||108|
|2014||Meta-analysis of observational studies||Non-significant effect of 25(OH)D concentrations on incidence of breast cancer||110||Breast cancer develops so rapidly that for follow-up times >3 year|
no significant inverse correlation is found
In the 1980s and 1990s it was realized that prevalence of type 1 diabetes mellitus (T1DM) had a latitudinal gradient, with highest rates in Europe in the Nordic countries 111, lower rates in Italy 112, and a significant increase with latitude in Sweden 113. A seven-country study in Europe found that “Vitamin D supplementation was associated with a decreased risk of Type I diabetes without indication of heterogeneity. The Mantel–Haenszel combined odds ratio was 0.67 (95% confidence limits: 0.53, 0.86)” 114. The case was made that vitamin D deficiency was a risk factor for autoimmune diseases, including T1DM, partly on the basis of the geographical variation in prevalence 115. Shortly thereafter, a study reported that infants at age 1 year in Finland who received 2000 IU/d of vitamin D had a very low risk of developing T1DM compared with the risk of those who did not take vitamin D supplements, whereas those with rickets had a risk of T1DM by age 31 years increased by a factor of three 116. Another ecological study in Australia also found a direct correlation between latitude and prevalence of T1DM 117. A later study in Western Australia found that “There was a strong latitudinal gradient of 3.5% (95% CI, 0.2–7.2) increased risk of T1DM per degree south of the Equator, as averaged across the range 15–35° south. This pattern is consistent with the hypothesis of vitamin D deficiency at higher latitudes. In addition there was a 2.4% (95% CI, 1.3–3.6) average increase in T1DM incidence per year” 118. The observed increase is probably due to the success of the campaign to reduce UV exposure in Australia to try to reduce the incidence of skin cancer and melanoma 119. A prospective 5.4-year study of U.S. military personnel associated serum 25(OH)D concentrations >100 nmol/L with a 44% reduced incidence rate of T1DM, compared with concentrations<75 nmol/L 120. A meta-analysis associated vitamin D supplementation in infancy with reduced risk of T1DM, but no such association existed for maternal vitamin D supplementation during pregnancy 121.
An animal model study showed that 1,25(OH)2D prevents and ameliorates symptoms of experimental murine inflammatory bowel disease (IBD) 115. Vitamin D's role in reducing risk of autoimmune disorders, including IBD, was outlined in 2001 122. Its role in reducing risk of IBD was outlined in 2005 123. In the United States, rates for Crohn's disease (CD) and ulcerative colitis are highest in the northeast and lowest in the south for children and lowest in the south for adults 124, 125, 126. Colitis caused by the bacterium Clostridium difficileis highly correlated with both prevalence and mortality rates by state for CD and ulcerative colitis in the United States, suggesting a pathological link 126, 127. A clinical study found a reduced relapse rate with vitamin D supplementation for those with CD 128. Predicted 25(OH)D concentration was inversely correlated with incidence of CD 127. A study in France inversely correlated residential sun exposure with incidence of CD 129. A meta-analysis found that IBD patients generally have low 25(OH)D concentrations 130.
Systemic lupus erythematosus (SLE) is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue. SLE can affect the skin, joints, kidneys, brain, and other organs 131. Cutaneous lupus erythematosus (CLE) manifests as reddening of the skin but may also involve organs and may be associated with SLE 132. It was known before 1965 that peoplewith lupus had adverse reactions to UV radiation 133. A U.S. ecological study reported that in 10 selected clusters, lupus mortality rates were higher in northern states than southern states and that Hispanic heritage and poverty explained much of the additional variance 134. A letter to the editor pointed out that the north–south difference was related to solar UVB doses 135. The ecological study was later extended with the finding that UVB radiation doses, Hispanic population, and poverty explained more than half of the geographical variation of lupus mortality rates in the 10 clusters 136. Incidence of lupus nephritis decreases with latitude in China by approximately a factor of three from 20° N to 45° N 137. A study in Hefei, China (32° N) found that SLE activity was lowest in autumn and correlated most strongly with sunshine duration 138. A recent paper reported that people with SLE have increased risk for many types of cancer 139. The likely explanation was that people with SLE tend to avoid sun exposure and, as a result, have lower 25(OH)D concentrations.
In addition, 25(OH)D concentration has been inversely correlated with disease activity of CLE 140 and SLE 141. Thus, supplementing people with lupus with vitamin D would seem sensible 142. In fact, vitamin D was used to treat lupus as early as 1950 143. Recent clinical trials have found beneficial effects on disease activity of vitamin D supplementation in CLE patients 144, in SLE patients in restoring regulatory and effector T-cell balance and B-cell homeostasis 145, and on inflammatory and hemostatic markers and disease activity 146.
The increase in MS prevalence with latitude has been known for many years 147, 148. The first suggestion that vitamin D deficiency was a possible cause of MS appears to have been made in 1960 by Acheson 147. Wintertime UVB exposure was more important than summertime UVB exposure in reducing risk of MS in Australia 149. Vitamin D supplementation reduced MS relapse rates 150. Munger and colleagues linked low 25(OH)D concentrations to risk of MS 151. More recently, a Mendelian randomization study involving a Canadian and an international cohort, only single nucleotide polymorphisms (SNPs) involved in 25(OH)D synthesis or metabolism were strongly inversely correlated with MS susceptibility 152. Animal studies have found that UV exposure reduces risk of MS in an animal model independently of vitamin D production 153. Some support exists for an independent role of UVB in human studies in Australia, although it cannot be ruled out that the effects attributed to UVB were not, in fact, due to vitamin D production 154. A more recent paper from Australia associated reported sun exposure, not 25(OH)D concentration, with reduced depressive symptoms and fatigue for people with MS 155.
High-dose vitamin D was used to treat rheumatoid arthritis (RA) in the 1940s 156. Unfortunately, the dose was often too high, up to 200,000 IU/d for a year, such that hypercalcemia developed 157. A later study found that oral high-dose 1,25(OH)2D3had a positive effect on disease activity for 89% of patients 158. The Iowa Women's Health Study associated higher oral intake of vitamin D with incidence of RA 159. Several studies have found an inverse correlation between 25(OH)D concentrations and RA activity levels 160, 161, 162. A study in Rome found that people with hypovitaminosis D responded less well to treatment than others, suggesting that vitamin D supplementation would help 163.
No latitudinal gradient was found for RA prevalence in Australia in 1995 117. In France, “The highest regional rates of RA were observed in the south (range 0.59–0.66%), and the lowest in the north (range 0.14–0.24%), with a national rate of 0.31% (95% CI 0.18–0.48%).” 164. However, the Nurses' Health Study found a significantly increased risk of incident RA for women living in the northeast U.S. for women aged 30–55 years in 1976 165 and again based on location in 1988 at an older age 166. The Nurses' Health Study also associated higher ambient UVB doses with a 21% lower risk of incident RA for women aged 30–55 years in 1976, but not in women aged 25–42 years in 1989 167. The lack of association for the later study was attributed to increased sun-protective behaviors. Thus, evidence appears to exist for an inverse correlation between incidence or prevalence of RA and solar UVB doses only in the U.S. Evidently, factors other than UVB exposure and vitamin D play important roles in the etiology of RA and, since the risk factors for RA are not well known, may not have been included in the studies.
The epidemiological evidence for a role of vitamin D comes largely from studies of the geographical variations in anaphylactic symptoms and seasonality of births among children with food allergies. The first epidemiological study was ecology-based on regional differences in U.S. EpiPen prescriptions in 2004 168. The highest rates were in the northeast (8–12 prescriptions/1000 people), whereas the lowest rates were in the southwest (2–3 prescriptions/1000 people). Anaphylaxis rates are inversely correlated with solar UVB doses in the U.S., which is highest in the southwest and lowest in the northeast 169, 170. The distribution is highly asymmetric for three reasons: higher surface elevations and thinner stratospheric ozone layer in the west and higher aerosol and cloud loading in the northeast. The thin ozone layer is due to the prevailing westerly winds crossing the Rocky Mountains and pushing the tropopause higher.
A similar study in Australia found a significant increase in EpiPen prescription rates going from 20° S to 45° S 171. Because Australia has no mountain ranges, solar UVB doses decrease with increasing latitude. Other factors did not significantly affect the finding. A related study in Australia also found higher use rates of hypoallergenic formula for infants in the southern and eastern regions 171. A study of visits to U.S. emergency departmentsfor acute allergic reactions found the highest rates in the northeast, with a stronger association seen when the reactions were limited to those caused by food allergy 172. More recently, a study in Chile also associated increasing latitude and decreasing solar UVB doses with increased risk of anaphylaxis in children 173. A recent paper reviewed how vitamin D's immune-modulatory actions on food allergy are related to “the vitamin D receptor and enzymes in monocytes, dendritic cells, epithelial cells, T lymphocytes and B lymphocytes” 174.
Eczema is an inflammatory condition of the skin characterized by redness, itching, and oozing vesicular lesions which become scaly, crusted, or hardened (www.merriam-webster.com/dictionary/eczema). Atopic dermatitis is the most common of the many types of eczema.
Phototherapy using UVA radiation treated atopic dermatitis in the 1970s 175, and combination UVA–UVB phototherapy was used in the 1980s 176. Evidently the search for the risk factors related to UV exposure did not begin until much later. A study in 12 European countries found that the prevalence of eczema symptoms increased with latitude and decreased with mean annual temperature 177. A study in Italy found that seaside holidays led to complete resolution of atopic dermatitis in 91% of patients, supporting the hypothesis that UV exposure benefited those with the disease 178. A study of children living on Australia's eastern seaboard found significant higher incidence of eczema in the central and southern regions than in the northern region 179. A U.S. study involving 91,642 children found significantly increased prevalence of eczema associated with several measures of lower solar UVB dose 180.
At least three clinical trials have examined vitamin D supplementation and atopic dermatitis in adults. Although the two conducted in Iran found beneficial effects 181, 182, the one conducted in the U.S. did not 183. A clinical trial in children in Mongolia found that taking 1000 IU/d of vitamin D3 for a month in winter reduced the eczema score by about 50% 44. The successful trials were conducted on populations with low 25-hydroxyvitamin D [25(OH)D] concentration, whereas the unsuccessful trial was conducted on a population with a baseline 25(OH)D concentration of 71 nmol/L. As a study of vitamin D trials on biomarkers of inflammation showed, baseline 25(OH)D concentrations should be below 50 nmol/L to yield a 50% chance of significant effects 184.
A recent review found that the evidence was inconclusive whether vitamin D status affects the development of atopic eczema 185. The evidence regarding maternal 25(OH)D concentration and development of infant eczema were considered inconsistent. However, two studies did find inverse correlations between cord blood 25(OH)D concentration and infant eczema—one with a mean 25(OH)D concentration of 58.4 nmol/L 186 and the other with 44.5 nmol/L 187. However, cord blood 25(OH)D concentrations were similar in the studies that did not find an inverse correlation (Table 1 in Ref. 185).
In summary, UV exposure is inversely correlated with risk of atopic dermatitis and eczema and is used to treat these diseases. Vitamin D trials involving people with low baseline 25(OH)D concentrations reduce the symptoms. Incidence of atopic eczema with respect to cord blood 25(OH)D concentration is mixed, but 25(OH)D concentration after birth might have a greater influence on risk. It cannot be ruled out that non–vitamin D effects of UV exposure can reduce risk and symptoms. However, a search of pubmed.gov found no mechanisms other than vitamin D production that might explain UV phototherapy's mechanism of action.
The first study reporting a possible relation between attention hyperactivity disorder (ADHD) and vitamin D was a 2013 ecological study 188. Figure 1 in that paper showed lowest rates of ADHD in the southwest and highest rates in the southeast. It also showed solar radiation for the U.S. with highest intensity in the southwest and lowest in the northeast. The authors considered vitamin D an explanation, but they could not find supporting evidence in the journal literature for either ADHD or autism. Instead, they suggested that bright sunlight disturbed sleep. I pointed out my paper showing that autism prevalence was inversely correlated with solar UVB 189. The evidence regarding vitamin D was published after that study. A case–control study in Qatar found that children with ADHD had a mean 25(OH)D concentration of 41.5 nmol/L, compared with 58.8 nmol/L for controls 190. A similar study in Turkey found that children with ADHD had a mean 25(OH)D concentration of 52.3 nmol/L, compared with 87.3 nmol/L for controls 191. A study in Spain of mother–child pairs found significant inverse correlations between maternal 25(OH)D concentration at 13 weeks' gestation and ADHD symptoms at age 4–5 years 192. Another birth-related study found a greatly increased risk of ADHD for extremely preterm birth in Australia 193. Maternal vitamin D deficiency is a risk factor for preterm birth 194. A study in China found that children with ADHD had a mean 25(OH)D concentration of 42.5 nmol/L, compared with 57.5 nmol/L for controls 195. Finally, a recent paper proposed a model “whereby insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression” 196. Thus, strong observational evidence indicates that low 25(OH)D concentration is a risk factor for ADHD, along with a model to explain why. However, since most of the studies were cross-sectional, having ADHD may have led to actions that resulted in lower 25(OH)D concentrations. Thus, having clinical trials to show that vitamin D reduces risk of ADHD would be helpful.
John Cannell proposed that vitamin D reduced risk of autism. He based that assertion in part on higher prevalence of autism in regions with lower sunlight, whether due to latitude or clouds 197. A later paper reported higher autism rates in regions of the U.S. West Coast with higher precipitation rates 198. Children with autism generally have lower 25(OH)D concentrations 199. Reviews of vitamin D and autism have been published 200, 201. A recent ecological study of autism prevalence among those aged 6–17 years found significant inverse correlations with respect to solar UVB doses 189. A study in Australia found that maternal 25(OH)D concentration <49 nmol/L at 18 weeks of pregnancy was associated with a significantly increased risk of the offspring being diagnosed with autism 202. In 2013, Cannell raised the question, Will vitamin D treat the core symptoms of autism? 203. Several papers have reported that the answer is yes 80, 204. A recent paper reported that parental and child alleles of the vitamin D receptor were significantly correlated with risk of autism, as was, in children, an allele of CYP2R1. That gene encodes production of 25-hydroxylase, the enzyme that converts vitamin D to 25(OH)D 205. A recent paper analyzed how vitamin D could affect risk of autism through its effects on tryptophan and serotonin production 206.
A study in Great Britain first reported an increase in lower back pain with increasing latitude 207. Vitamin D deficiency was reported as a risk factor for nonspecific lower back pain in 2003 208, 209. In a study in Saudi Arabia, those with lower back pain treated with vitamin D reported significant reductions in back pain 208. Data on lumbar pain in Southeast Asian countries indicates an increasing rate from Malaysia (5° N) (8.8%) through 23° N (13%), 32° N (15.8%) to Beijing (40° N) (35%) 210. A letter to the editor linked the findings of the recent global survey of lower back pain 211 to overweight/obesity and vitamin D deficiency 212. A clinical trial conducted in Israel found that taking 4000 IU/d of vitamin D3 significantly reduced inflammatory and pain-related cytokines for patients with musculoskeletal pain 213.
An ecological study found a significant inverse correlation between latitude and hypertension, suggesting that UV radiation reduced blood pressure 214. Risk of developing hypertension has been found inversely correlated with 25(OH)D concentration 215, 216. Many prospective and cross-sectional studies found that 25(OH)D concentrations were inversely correlated with incidence and prevalence of hypertension for younger, but not elderly, participants 217. A Mendelian randomization study found a minor effect of vitamin D genes on blood pressure and a 10% reduced risk of hypertension 218. However, clinical trials offer little support for vitamin D in reducing blood pressure 219.
An alternative hypothesis is that long-wave UV (UVA) reduces blood pressure, evidently through release of nitric oxide from endothelial nitric oxide synthase 6, 220 as well as through other mechanisms 221. If one combines the findings from the two approaches, low 25(OH)D concentrations may be due to UVB exposure, with nitric oxide actually reducing blood pressure.
Using age-adjusted death rate data from1959–1961, Kurtzke and Goldberg found that both white and black Americans had higher Parkinson's disease (PD) death rates in northern U.S. states than in southern states 222. Using mortality rate data for 1988, that study found that the north–south pattern for whites persisted, but not for blacks 223. What had happened is that black Americans worked less on farms in the south in the latter generation, with many moving north to work in automobile and other factories. The UVB–vitamin D–PD hypothesis was apparently proposed in part on the basis of the higher rate of PD in the northern states 224. Outdoor work has also been associated with reduced risk of PD 225. A 29-year follow-up study in Finland involving 3173 men and women, among whom 50 developed PD, found a relative risk between highest and lowest 25(OH)D quartiles of 0.33 (95% CI = 0.14–0.80) 226. A U.S. study found that people with early-stage PD have lower 25(OH)D concentrations 227. A study in China found a significant inverse correlation between 25(OH)D concentration and severity of PD 221.
The history of the understanding of rickets was reviewed in 228. In the 17th century, rickets was due to lack of sunshine caused by living in cities with heavy smog 229. However, whether this fact was understood then is unclear. The first study of the geographical variation of rickets rates was published in 1890230. By 1921, research showed that sunlight and artificial UV could cure rickets 231—and in 1922, vitamin D was identified as the active agent in preventing rickets 232.
Table 3 summarizes the major findings regarding geographical variations in disease rates, correlations with 25(OH)D concentrations, clinical trials, and hypotheses regarding UV exposure and vitamin D in keeping with the discussion to this point. In some cases, ecological studies preceded observational studies, such as for autism, several cancers, MS, and RSV, whereas in other cases observational studies came first but ecological studies offered more support for the role of solar UVB and vitamin D in reducing risk of disease. The studies identified are thought to be correct, but there may be some inadvertent omissions.
Table 3 Pioneering studies regarding ecological and observational studies and clinical trials for diseases reviewed in this paper.
|Disease||Latitude but |
due to UVB
and vitamin D
|Dental caries||1965 (233)||1939 (19)||1928 (17)||1928 (17)|
|Pneumonia||2009 (30)||1997 (29)|
|Respiratory syncytial virus||2007 (33)||2011 (35)|
|Sepsis||2009 (39)||1987 (234)|
|UV as risk factor; skin||1944 (45)|
|Lip and salivary gland||1988 (50))|
|Cervical and pharyngeal cancer||2104 (54)|
|Cancer||1941 (99)||1980 (66)||2007 (70)|
|Breast||1990 (103)||1989 (235)||2005 (236)||2011 (96)|
|Colon||1980 (66)||1980 (66)||1989 (68)||2011(96)|
|Ovarian||1994 (237)||1994 (237)||2010 (238)|
|Pancreatic||1985 (102)||2002 (63)||2006 (69)|
|Prostate||1990 (82)||1990 (82)||1993 (239)|
|Non-Hodgkin's lymphoma||1996(240,241)||2002 (63)|
|Crohn's disease||2007 (124)||2005 (123)|
|Diabetes mellitus type 1||1985 (111)||20001 (15)||1997(242)|
|Lupus||2001 (134)||2003 (135)||1995 (243)||2014 (144)|
|Multiple sclerosis||1960 (147)||1978 (244)||2006 (151)|
|Rheumatoid arthritis||2008 (165)||2004 (159)|
|Anaphylaxis||2007 (168)||2007 (168)|
|2013 (188)||2013 (245)||2014 (190)|
|Atopic dermatitis||2004 (177)||2011 (181)|
|Autism||2008 (197)||2008 (197)||2012 (199)||2015(80, 204)|
|Lower back pain||1992 (207)||2003 (208, 209)||2003 (208, 209)||2015 (213)|
|Parkinson's disease||1988 (222)||2007 (224)||2010 (226)|
|Rickets||1890 (230)||1922 (232)|
Critics often use the term ecological fallacy to disparage ecological studies. However, linking that term solely to ecological studies is incorrect. According to the Web Center for Social Research Methods, “The ecological fallacy occurs when you make conclusions about individuals based only on analyses of group data. For instance, assume that you measured the math scores of a particular classroom and found that they had the highest average score in the district.” [http://www.socialresearchmethods.net/kb/fallacy.php]. Other examples exist, such as assuming that various pharmaceutical drugs, which were found to have a significant beneficial effect for the group tested may, in fact, have detrimental effects for some individuals. For example, taking aspirin can reduce the risk of cancer and cardiovascular disease, but doing so entails the risk of internal bleeding 246. Also, there are about 20 genes that affect about 80 medications or about 7% of FDA-approved medications 247. The choice of population for any type of epidemiological study may substantially affect the outcome, which could be due to differences in religious practices, diet, lifestyle, and/or genetics. For example, a study recently linked the fact that the Inuit thrive on a high-fat diet to the genetic adaptation of living in a cold environment 248. Several papers have discussed multilevel analyses, that is, results based on studies of groups and individuals, and how to assess the findings as the basis for public health policies 249, 250, 251.
A few recent papers suggest that health benefits of UVB exposure may be independent of or in addition to those from vitamin D production. Some such studies were discussed with respect to outcomes such as MS. While reviewing that body of literature is not the intention, a few of these reviews appear in the following papers: 252,253, 254, 255,256.
Some vitamin D–sensitive diseases such as influenza 257 and cardiovascular disease (CVD) 258 have pronounced seasonal variations, generally higher in winter 257,130, but do not exhibit geographical variations related to solar UVB doses. For influenza, the seasonal variation is due to seasonal variations not only in solar UVB doses 257 but also in temperature and relative humidity 259. For CVD, significant associations are present with PM2.5 particular matter concentrations in the U.S. 260,261. Although 25(OH)D concentration is inversely correlated with incidence of CVD 262, the geographical variation of many other CVD-modifying risk factors (such as smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose) evidently plays a more important role in determining the geographical variation 263.
Given the advantages of the ecological approach, such as large number of cases and ready availability of public-access data sets for both health outcomes and risk-modifying factors, it should be used more widely. One application might be to identify additional health outcomes related to geographic variations in solar UVB doses. However, a more important application might be to monitor trends in health conditions linked to UV exposure and vitamin D. For example, breast cancer incidence and/or mortality rate patterns in the U.S. have changed dramatically since the 1950s 83, (http://ratecalc.cancer.gov/), with the characteristic inverse relation to solar UVB dose in July being less pronounced in recent years (http://ratecalc.cancer.gov/). Although some of the factors responsible for changes include mammographic screening and changes in hormone replacement therapy 264, 25(OH)D concentrations may also have decreased owing to spending more time indoors and using sunscreen when outdoors 265.
Ecological studies have been used in cancer prevention research for many years, identifying both dietary factors 3,7 and solar UVB/vitamin D 66,76 as important risk-modifying factors and providing estimates of the effects. Although clinical trials are the most appropriate approach for assessing the benefits—if not the risks—of pharmaceutical drugs, they may not be for both diet and UVB/vitamin D. Alan Kristal outlined the problems with clinical trials for cancer prevention. Those problems include appropriate doses, compliance, the long durations required, and personal choice changes due to widely publicized health findings 266. To his list should also be added the small number of cases due to the costs of large trials, as well as the fact that the population chosen may not be appropriate for assessing the effects on other populations.
Geographical ecological studies of health outcomes with respect to solar UVB doses have made important contributions to the understanding of the roles of UVB exposure and vitamin D in reducing risk of many types of disease. In many cases, ecological studies were the first to make such connections and leading to other types of studies that confirmed and extended the findings. Such ecological studies will continue to provide useful information such as regarding trends in diseases with respect to changes in UVB exposures and the relative contributions of UVB exposure and other risk-modifying factors in health outcomes.
- 1. Rajakumar K, Greenspan SL, Thomas SB, Holick MF. SOLAR ultraviolet radiation and vitamin D: a historical perspective. American journal of public health 2007; 97:1746-54. [CrossRef], [PubMed], [Web of Science ®]
- 2. Knox JF, Holmes S, Doll R, Hill ID. Mortality from lung cancer and other causes among workers in an asbestos textile factory. Br J Ind Med 1968; 25:293-303. [PubMed]
- 3. Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. International journal of cancer Journal international du cancer 1975; 15:617-31. [CrossRef], [PubMed], [Web of Science ®]
- 4. Cameli M, Khayyal M, Marino F, Augustine D, Forshaw T, Mondillo S, Stankovic I, Surkova E, Timeshova T, Vasco N, et al. Club 35 EACVI web spotlight: comments on right ventricle assessment in the new echocardiography recommendations. Eur Heart J Cardiovasc Imaging 2015. [Web of Science ®]
- 5. Cho E, Chen WY, Hunter DJ, Stampfer MJ, Colditz GA, Hankinson SE, Willett WC. Red meat intake and risk of breast cancer among premenopausal women. Archives of internal medicine 2006; 166:2253-9. [CrossRef], [PubMed], [Web of Science ®]
- 6. Oplander C, Volkmar CM, Paunel-Gorgulu A, van Faassen EE, Heiss C, Kelm M, Halmer D, Murtz M, Pallua N, Suschek CV. Whole body UVA irradiation lowers systemic blood pressure by release of nitric oxide from intracutaneous photolabile nitric oxide derivates. Circulation research 2009; 105:1031-40. [PubMed], [Web of Science ®]
- 7. Grant WB. A multicountry ecological study of cancer incidence rates in 2008 with respect to various risk-modifying factors. Nutrients 2014; 6:163-89. [Web of Science ®]
- 8. Grant WB. Dietary links to Alzheimer's disease. Alz Dis Rev 1997; 2:42-55.
- 9. Luchsinger JA, Tang MX, Shea S, Mayeux R. Caloric intake and the risk of Alzheimer disease. Arch Neurol 2002; 59:1258-63. [CrossRef], [PubMed]
- 10. Barberger-Gateau P, Letenneur L, Deschamps V, Peres K, Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study. BMJ 2002; 325:932-3. [CrossRef], [PubMed], [Web of Science ®]
- 11. Grant WB. Trends in diet and Alzheimer's disease during the nutrition transition in Japan and developing countries. Journal of Alzheimer's disease : JAD 2014; 38:611-20. [PubMed], [Web of Science ®]
- 12. Uribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, Yong A, Striker GE, Vlassara H. Advanced glycation end products in foods and a practical guide to their reduction in the diet. Journal of the American Dietetic Association 2010; 110:911-16 e12. [CrossRef], [PubMed], [Web of Science ®]
- 13. Perrone L, Grant WB. Observational and Ecological Studies of Dietary Advanced Glycation End Products in National Diets and Alzheimer's Disease Incidence and Prevalence. Journal of Alzheimer's disease : JAD 2015. [PubMed], [Web of Science ®]
- 14. Mosconi L, McHugh PF. Let Food Be Thy Medicine: Diet, Nutrition, and Biomarkers' Risk of Alzheimer's Disease. Curr Nutr Rep 2015; 4:126-35. [CrossRef], [PubMed]
- 15. Xu W, Tan L, Wang HF, Jiang T, Tan MS, Tan L, Zhao QF, Li JQ, Wang J, Yu JT. Meta-analysis of modifiable risk factors for Alzheimer's disease. J Neurol Neurosurg Psychiatry 2015. [Web of Science ®]
- 16. Lewis JM, Wilson LT. Vitamin A requirements in calves. The Journal of nutrition 1945; 30:467-75. [PubMed]
- 17. Mellanby M, Pattison CL. The Action of Vitamin D in Preventing the Spread and Promoting the Arrest of Caries in Children. British medical journal 1928; 2:1079-82. [CrossRef], [PubMed]
- 18. Grant WB. A review of the role of solar ultraviolet-B irradiance and vitamin D in reducing risk of dental caries. Dermato-endocrinology 2011; 3:193-8. [Taylor & Francis Online], [PubMed]
- 19. East BR. Mean Annual Hours of Sunshine and the Incidence of Dental Caries. American journal of public health and the nation's health 1939; 29:777-80. [CrossRef], [PubMed]
- 20. Hadjimarkos DM. Geographic variations of dental caries in Oregon. VII. Caries prevalence among children in the Blue Mountains region. The Journal of pediatrics 1956; 48:195-201. [CrossRef], [PubMed], [Web of Science ®]
- 21. Dunning JM. The influence of latitude and distance from seacoast on dental disease. Journal of dental research 1953; 32:811-29. [CrossRef], [PubMed], [Web of Science ®]
- 22. Hujoel PP. Vitamin D and dental caries in controlled clinical trials: systematic review and meta-analysis. Nutrition reviews 2013; 71:88-97. [CrossRef], [PubMed], [Web of Science ®]
- 23. Lindberg C, Andersen O, Vahlne A, Dalton M, Runmarker B. Epidemiological investigation of the association between infectious mononucleosis and multiple sclerosis. Neuroepidemiology 1991; 10:62-5. [PubMed], [Web of Science ®]
- 24. Goldacre MJ, Wotton CJ, Seagroatt V, Yeates D. Multiple sclerosis after infectious mononucleosis: record linkage study. Journal of epidemiology and community health 2004; 58:1032-5. [CrossRef], [PubMed], [Web of Science ®]
- 25. Ramagopalan SV, Hoang U, Seagroatt V, Handel A, Ebers GC, Giovannoni G, Goldacre MJ. Geography of hospital admissions for multiple sclerosis in England and comparison with the geography of hospital admissions for infectious mononucleosis: a descriptive study. J Neurol Neurosurg Psychiatry 2011; 82:682-7. [PubMed], [Web of Science ®]
- 26. Lossius A, Riise T, Pugliatti M, Bjornevik K, Casetta I, Drulovic J, Granieri E, Kampman MT, Landtblom AM, Lauer K, et al. Season of infectious mononucleosis and risk of multiple sclerosis at different latitudes; the EnvIMS Study. Mult Scler 2014; 20:669-74. [PubMed], [Web of Science ®]
- 27. Sumaya CV, Ench Y. Epstein-Barr virus infections in families: the role of children with infectious mononucleosis. The Journal of infectious diseases 1986; 154:842-50. [CrossRef], [PubMed], [Web of Science ®]
- 28. Correale J, Gaitan MI. Multiple sclerosis and environmental factors: the role of vitamin D, parasites, and Epstein-Barr virus infection. Acta Neurol Scand Suppl 2015; 132:46-55.
- 29. Muhe L, Lulseged S, Mason KE, Simoes EA. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet 1997; 349:1801-4. [CrossRef], [PubMed], [Web of Science ®]
- 30. Grant WB, Giovannucci E. The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918–1919 influenza pandemic in the United States. Dermato-endocrinology 2009; 1:215-9. [Taylor & Francis Online], [PubMed]
- 31. Quraishi SA, Bittner EA, Christopher KB, Camargo CA, Jr. Vitamin D status and community-acquired pneumonia: results from the third National Health and Nutrition Examination Survey. PloS one 2013; 8:e81120. [PubMed]
- 32. Pletz MW, Terkamp C, Schumacher U, Rohde G, Schutte H, Welte T, Bals R, Group CA-S. Vitamin D deficiency in community-acquired pneumonia: low levels of 1,25(OH)2 D are associated with disease severity. Respir Res 2014; 15:53. [CrossRef], [PubMed], [Web of Science ®]
- 33. Yusuf S, Piedimonte G, Auais A, Demmler G, Krishnan S, Van Caeseele P, Singleton R, Broor S, Parveen S, Avendano L, et al. The relationship of meteorological conditions to the epidemic activity of respiratory syncytial virus. Epidemiology and infection 2007; 135:1077-90. [CrossRef], [PubMed], [Web of Science ®]
- 34. Hansdottir S, Monick MM, Lovan N, Powers L, Gerke A, Hunninghake GW. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol 2010; 184:965-74. [CrossRef], [PubMed], [Web of Science ®]
- 35. Belderbos ME, Houben ML, Wilbrink B, Lentjes E, Bloemen EM, Kimpen JL, Rovers M, Bont L. Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Pediatrics 2011; 127:e1513-20. [CrossRef], [PubMed], [Web of Science ®]
- 36. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311:1770-3. [CrossRef], [PubMed], [Web of Science ®]
- 37. Mookherjee N, Rehaume LM, Hancock RE. Cathelicidins and functional analogues as antisepsis molecules. Expert Opin Ther Targets 2007; 11:993-1004. [Taylor & Francis Online], [PubMed], [Web of Science ®]
- 38. Danai PA, Sinha S, Moss M, Haber MJ, Martin GS. Seasonal variation in the epidemiology of sepsis. Crit Care Med 2007; 35:410-5. [CrossRef], [PubMed], [Web of Science ®]
- 39. Grant WB. Solar ultraviolet-B irradiance and vitamin D may reduce the risk of septicemia. Dermato-endocrinology 2009 in press; 1.
- 40. Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, Tangpricha V. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med 2009; 7:28. [CrossRef], [PubMed], [Web of Science ®]
- 41. Kempker JA, Martin GS. Vitamin D and sepsis: from associations to causal connections. Inflamm Allergy Drug Targets 2013; 12:246-52. [PubMed]
- 42. Quraishi SA, Litonjua AA, Moromizato T, Gibbons FK, Camargo CA, Jr., Giovannucci E, Christopher KB. Association between prehospital vitamin D status and hospital-acquired bloodstream infections. The American journal of clinical nutrition 2013; 98:952-9. [PubMed], [Web of Science ®]
- 43. Jovanovich AJ, Ginde AA, Holmen J, Jablonski K, Allyn RL, Kendrick J, Chonchol M. Vitamin D level and risk of community-acquired pneumonia and sepsis. Nutrients 2014; 6:2196-205. [PubMed], [Web of Science ®]
- 44. Amrein K, Quraishi SA, Litonjua AA, Gibbons FK, Pieber TR, Camargo CA, Jr., Giovannucci E, Christopher KB. Evidence for a U-shaped relationship between prehospital vitamin D status and mortality: a cohort study. The Journal of clinical endocrinology and metabolism 2014; 99:1461-9. [PubMed], [Web of Science ®]
- 45. Dorn HF. Tobacco consumption and mortality from cancer and other diseases. Acta Unio Int Contra Cancrum 1960; 16:1653-65. [PubMed]
- 46. Auerbach H. Geographic variation in incidence of skin cancer in the United States. Public Health Rep 1961; 76:345-8. [PubMed], [Web of Science ®]
- 47. Rivas M, Rojas E, Calaf GM. Prediction of skin cancer occurrence by ultraviolet solar index. Oncol Lett 2012; 3:893-6. [PubMed], [Web of Science ®]
- 48. Wheeler BW, Kothencz G, Pollard AS. Geography of non-melanoma skin cancer and ecological associations with environmental risk factors in England. British journal of cancer 2013; 109:235-41. [CrossRef], [PubMed], [Web of Science ®]
- 49. Moan J, Porojnicu AC, Dahlback A. Ultraviolet radiation and malignant melanoma. Advances in experimental medicine and biology 2008; 624:104-16. [CrossRef], [PubMed], [Web of Science ®]
- 50. Spitz MR, Sider JG, Newell GR, Batsakis JG. Incidence of salivary gland cancer in the United States relative to ultraviolet radiation exposure. Head Neck Surg 1988; 10:305-8. [PubMed]
- 51. Spitz MR, Sider JG, Newell GR. Salivary gland cancer and risk of subsequent skin cancer. Head Neck 1990; 12:254-6. [PubMed], [Web of Science ®]
- 52. Hakansson N, Floderus B, Gustavsson P, Feychting M, Hallin N. Occupational sunlight exposure and cancer incidence among Swedish construction workers. Epidemiology 2001; 12:552-7. [PubMed], [Web of Science ®]
- 53. Grant WB. Ultraviolet exposure and non-Hodgkin's lymphoma: beneficial and adverse effects? Cancer causes & control : CCC 2012; 23:653-5; author reply 7-8. [PubMed], [Web of Science ®]
- 54. Godar DE, Tang R, Merrill SJ. Pharyngeal and cervical cancer incidences significantly correlate with personal UV doses among whites in the United States. Anticancer research 2014; 34:4993-9. [PubMed], [Web of Science ®]
- 55. Hrushesky WJ, Sothern RB, Rietveld WJ, Du Quiton J, Boon ME. Season, sun, sex, and cervical cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2005; 14:1940-7. [PubMed], [Web of Science ®]
- 56. Hrushesky WJ, Sothern RB, Rietveld WJ, Du-Quiton J, Boon ME. Sun exposure, sexual behavior and uterine cervical human papilloma virus. Int J Biometeorol 2006; 50:167-73. [PubMed], [Web of Science ®]
- 57. Grant WB, Garland CF. The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer research 2006; 26:2687-99. [PubMed], [Web of Science ®]
- 58. Astbury A. Non uniformity in cancer mortality in the USA and Australia appears to share a common origin. Vancouver, BC TRIUMF, 2005.
- 59. Tran B, Whiteman DC, Webb PM, Fritschi L, Fawcett J, Risch HA, Lucas R, Pandeya N, Schulte A, Neale RE. Association between ultraviolet radiation, skin sun sensitivity and risk of pancreatic cancer. Cancer epidemiology 2013; 37:886-92. [CrossRef], [PubMed], [Web of Science ®]
- 60. Chen W, Clements M, Rahman B, Zhang S, Qiao Y, Armstrong BK. Relationship between cancer mortality/incidence and ambient ultraviolet B irradiance in China. Cancer causes & control : CCC 2010; 21:1701-9. [CrossRef], [PubMed], [Web of Science ®]
- 61. Grant WB. An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. Dermato-endocrinology 2010; 2:62-7. [Taylor & Francis Online], [PubMed]
- 62. Grant WB. An ecologic study of cancer mortality rates in Spain with respect to indices of solar UVB irradiance and smoking. International journal of cancer Journal international du cancer 2007; 120:1123-8. [CrossRef], [PubMed], [Web of Science ®]
- 63. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 2002; 94:1867-75. [CrossRef], [PubMed], [Web of Science ®]
- 64. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993–2002. BMC cancer 2006; 6:264. [CrossRef], [PubMed], [Web of Science ®]
- 65. Grant WB. Role of solar UVB irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermato-endocrinology 2012; 4:203-11. [Taylor & Francis Online], [PubMed]
- 66. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? International journal of epidemiology 1980; 9:227-31. [CrossRef], [PubMed], [Web of Science ®]
- 67. Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet 1985; 1:307-9. [CrossRef], [PubMed], [Web of Science ®]
- 68. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 1989; 2:1176-8. [CrossRef], [PubMed], [Web of Science ®]
- 69. Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, Willett WC. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. Journal of the National Cancer Institute 2006; 98:451-9. [CrossRef], [PubMed], [Web of Science ®]
- 70. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. The American journal of clinical nutrition 2007; 85:1586-91. [PubMed], [Web of Science ®]
- 71. Grant WB. 25-hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case-control versus nested case-control studies. Anticancer research 2015; 35:1153-60. [PubMed]
- 72. Mondul AM, Weinstein SJ, Mannisto S, Snyder K, Horst RL, Virtamo J, Albanes D. Serum vitamin D and risk of bladder cancer. Cancer research 2010; 70:9218-23. [PubMed], [Web of Science ®]
- 73. Tretli S, Schwartz GG, Torjesen PA, Robsahm TE. Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study. Cancer causes & control : CCC 2012; 23:363-70. [CrossRef], [PubMed], [Web of Science ®]
- 74. Wang W, Li G, He X, Gao J, Wang R, Wang Y, Zhao W. Serum 25-hydroxyvitamin D levels and prognosis in hematological malignancies: a systematic review and meta-analysis. Cell Physiol Biochem 2015; 35:1999-2005. [PubMed], [Web of Science ®]
- 75. Krishnan AV, Feldman D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annual review of pharmacology and toxicology 2011; 51:311-36. [CrossRef], [PubMed], [Web of Science ®]
- 76. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients 2013; 5:3993-4021. [CrossRef], [PubMed], [Web of Science ®]
- 77. Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G, Stattin P, Harvei S, Hakulinen T, Luostarinen T, et al. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. International journal of cancer Journal international du cancer 2004; 108:104-8. [CrossRef], [PubMed], [Web of Science ®]
- 78. Stolzenberg-Solomon RZ, Vieth R, Azad A, Pietinen P, Taylor PR, Virtamo J, Albanes D. A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers. Cancer research 2006; 66:10213-9. [CrossRef], [PubMed], [Web of Science ®]
- 79. Stolzenberg-Solomon RZ, Hayes RB, Horst RL, Anderson KE, Hollis BW, Silverman DT. Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial. Cancer research 2009; 69:1439-47. [CrossRef], [PubMed], [Web of Science ®]
- 80. Jia F, Wang B, Shan L, Xu Z, Staal WG, Du L. Core symptoms of autism improved after vitamin d supplementation. Pediatrics 2015; 135:e196-8. [PubMed], [Web of Science ®]
- 81. Nair-Shalliker V, Armstrong BK, Fenech M. Does vitamin D protect against DNA damage? Mutation research 2012; 733:50-7. [CrossRef], [PubMed], [Web of Science ®]
- 82. Schwartz GG, Hulka BS. Is vitamin D deficiency a risk factor for prostate cancer? (Hypothesis). Anticancer research 1990; 10:1307-11. [PubMed], [Web of Science ®]
- 83. Devesa SS, Grauman DJ, Blot WJ, Pennello GA, Hoover RN, Fraumeni JFJ. Atlas of Cancer Mortality in the United States, 1950–1994. NIH Publication No 99–4564: National Institute of Health, 1999.
- 84. Murray CJ, Kulkarni SC, Michaud C, Tomijima N, Bulzacchelli MT, Iandiorio TJ, Ezzati M. Eight Americas: investigating mortality disparities across races, counties, and race-counties in the United States. PLoS medicine 2006; 3:e260. [CrossRef], [PubMed], [Web of Science ®]
- 85. Wolpin BM, Ng K, Bao Y, Kraft P, Stampfer MJ, Michaud DS, Ma J, Buring JE, Sesso HD, Lee IM, et al. Plasma 25-hydroxyvitamin D and risk of pancreatic cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2012; 21:82-91. [CrossRef], [PubMed], [Web of Science ®]
- 86. Ensrud KE, Ewing SK, Fredman L, Hochberg MC, Cauley JA, Hillier TA, Cummings SR, Yaffe K, Cawthon PM. Circulating 25-hydroxyvitamin D levels and frailty status in older women. The Journal of clinical endocrinology and metabolism 2010; 95:5266-73. [CrossRef], [PubMed], [Web of Science ®]
- 87. Ensrud KE, Blackwell TL, Cauley JA, Cummings SR, Barrett-Connor E, Dam TT, Hoffman AR, Shikany JM, Lane NE, Stefanick ML, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. Journal of the American Geriatrics Society 2011; 59:101-6. [CrossRef], [PubMed], [Web of Science ®]
- 88. Kroll MH, Bi C, Garber CC, Kaufman HW, Liu D, Caston-Balderrama A, Zhang K, Clarke N, Xie M, Reitz RE, et al. Temporal relationship between vitamin D status and parathyroid hormone in the United States. PloS one 2015; 10:e0118108.
- 89. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. The lancet Diabetes & endocrinology 2014; 2:76-89. [CrossRef], [PubMed], [Web of Science ®]
- 90. Chowdhury R, Kunutsor S, Vitezova A, Oliver-Williams C, Chowdhury S, Kiefte-de-Jong JC, Khan H, Baena CP, Prabhakaran D, Hoshen MB, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ 2014; 348:g1903.
- 91. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ 2014; 348:g2035. [CrossRef], [PubMed], [Web of Science ®]
- 92. Ness RA, Miller DD, Li W. The role of vitamin D in cancer prevention. Chin J Nat Med 2015; 13:481-97. [CrossRef], [PubMed], [Web of Science ®]
- 93. Tagliabue E, Raimondi S, Gandini S. Vitamin D, Cancer Risk, and Mortality. Adv Food Nutr Res 2015; 75:1-52. [PubMed]
- 94. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutrition reviews 2014; 72:48-54. [CrossRef], [PubMed], [Web of Science ®]
- 95. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermato-endocrinology 2014; 6:e983401. [Taylor & Francis Online], [PubMed]
- 96. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. The American journal of clinical nutrition 2011; 94:1144-9. [CrossRef], [PubMed], [Web of Science ®]
- 97. Rebel H, der Spek CD, Salvatori D, van Leeuwen JP, Robanus-Maandag EC, de Gruijl FR. UV exposure inhibits intestinal tumor growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet. International journal of cancer Journal international du cancer 2015; 136:271-7. [CrossRef], [PubMed], [Web of Science ®]
- 98. Peller S, Stephenson CS. Skin irritation and cancer in the United states Navy. Am J Med Sci 1937; 194:326-33. [CrossRef]
- 99. Apperly FL. The relation of solar radiation to cancer mortality in North America. Cancer research 1941; 1:191-5.
- 100. Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, Yamazaki T, Yoshiki S, Suda T. Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D3. Proceedings of the National Academy of Sciences of the United States of America 1981; 78:4990-4.
- 101. Colston K, Colston MJ, Feldman D. 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology 1981; 108:1083-6. [CrossRef], [PubMed], [Web of Science ®]
- 102. Kato I, Tajima K, Kuroishi T, Tominaga S. Latitude and pancreatic cancer. Japanese journal of clinical oncology 1985; 15:403-13. [PubMed], [Web of Science ®]
- 103. Garland FC, Garland CF, Gorham ED, Young JF. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Preventive medicine 1990; 19:614-22. [CrossRef], [PubMed], [Web of Science ®]
- 104. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation. Cancer 1992; 70:2861-9. [CrossRef], [PubMed], [Web of Science ®]
- 105. Grant WB. 25-Hydroxyvitamin D and Breast Cancer, Colorectal Cancer, and Colorectal Adenomas: Case-Control versus Nested Case-Control Studies. Anticancer research 2015; 35:1153-60. [PubMed]
- 106. Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O'Sullivan MJ, Margolis KL, Ockene JK, Phillips L, Pottern L, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. The New England journal of medicine 2006; 354:684-96. [CrossRef], [PubMed], [Web of Science ®]
- 107. Helzlsouer KJ, Committee VS. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. American journal of epidemiology 2010; 172:4-9. [CrossRef], [PubMed], [Web of Science ®]
- 108. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level: Implications for meta-analyses and setting vitamin D guidelines. Dermato-endocrinology 2011; 3:199-204. [Taylor & Francis Online], [PubMed]
- 109. Weinstein SJ, Yu K, Horst RL, Ashby J, Virtamo J, Albanes D. Serum 25-hydroxyvitamin D and risks of colon and rectal cancer in Finnish men. American journal of epidemiology 2011; 173:499-508. [CrossRef], [PubMed], [Web of Science ®]
- 110. Kim Y, Je Y. Vitamin D intake, blood 25(OH)D levels, and breast cancer risk or mortality: a meta-analysis. British journal of cancer 2014; 110:2772-84. [CrossRef], [PubMed], [Web of Science ®]
- 111. Akerblom HK, Reunanen A. The epidemiology of insulin-dependent diabetes mellitus (IDDM) in Finland and in northern Europe. Diabetes care 1985; 8 Suppl 1:10-6. [PubMed]
- 112. Garancini P, Gallus G, Calori G, Formigaro F, Micossi P. Incidence and prevalence rates of diabetes mellitus in Italy from routine data: a methodological assessment. European journal of epidemiology 1991; 7:55-63. [PubMed], [Web of Science ®]
- 113. Nystrom L, Dahlquist G, Ostman J, Wall S, Arnqvist H, Blohme G, Lithner F, Littorin B, Schersten B, Wibell L. Risk of developing insulin-dependent diabetes mellitus (IDDM) before 35 years of age: indications of climatological determinants for age at onset. International journal of epidemiology 1992; 21:352-8. [PubMed], [Web of Science ®]
- 114. Barker ME, Thompson KA, McClean SI. Do type as eat differently? A comparison of men and women. Appetite 1996; 26:277-85. [PubMed], [Web of Science ®]
- 115. Cantorna MT.Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence? Proc Soc Exp Biol Med 2000; 223:230-3. [CrossRef], [PubMed], [Web of Science ®]
- 116. Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358:1500-3. [CrossRef], [PubMed], [Web of Science ®]
- 117. Staples JA, Ponsonby AL, Lim LL, McMichael AJ. Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence. Environmental health perspectives 2003; 111:518-23. [CrossRef], [PubMed], [Web of Science ®]
- 118. Ball SJ, Haynes A, Jacoby P, Pereira G, Miller LJ, Bower C, Davis EA. Spatial and temporal variation in type 1 diabetes incidence in Western Australia from 1991 to 2010: increased risk at higher latitudes and over time. Health Place 2014; 28:194-204. [PubMed], [Web of Science ®]
- 119. van der Mei IA, Ponsonby AL, Engelsen O, Pasco JA, McGrath JJ, Eyles DW, Blizzard L, Dwyer T, Lucas R, Jones G. The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude. Environmental health perspectives 2007; 115:1132-9. [CrossRef], [PubMed], [Web of Science ®]
- 120. Munger KL, Levin LI, Massa J, Horst R, Orban T, Ascherio A. Preclinical serum 25-hydroxyvitamin D levels and risk of type 1 diabetes in a cohort of US military personnel. American journal of epidemiology 2013; 177:411-9. [PubMed], [Web of Science ®]
- 121. Dong JY, Zhang WG, Chen JJ, Zhang ZL, Han SF, Qin LQ. Vitamin D intake and risk of type 1 diabetes: a meta-analysis of observational studies. Nutrients 2013; 5:3551-62. [CrossRef], [PubMed], [Web of Science ®]
- 122. Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2001; 15:2579-85. [CrossRef], [PubMed], [Web of Science ®]
- 123. Lim WC, Hanauer SB, Li YC. Mechanisms of disease: vitamin D and inflammatory bowel disease. Nat Clin Pract Gastroenterol Hepatol 2005; 2:308-15. [CrossRef], [PubMed]
- 124. Kappelman MD, Rifas-Shiman SL, Kleinman K, Ollendorf D, Bousvaros A, Grand RJ, Finkelstein JA. The prevalence and geographic distribution of Crohn's disease and ulcerative colitis in the United States. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2007; 5:1424-9. [CrossRef], [PubMed], [Web of Science ®]
- 125. Sonnenberg A. Demographic characteristics of hospitalized IBD patients. Digestive diseases and sciences 2009; 54:2449-55. [PubMed], [Web of Science ®]
- 126. Sonnenberg A. Similar geographic variations of mortality and hospitalization associated with IBD and Clostridium difficile colitis. Inflamm Bowel Dis 2010; 16:487-93.
- 127. Khalili H, Huang ES, Ananthakrishnan AN, Higuchi L, Richter JM, Fuchs CS, Chan AT. Geographical variation and incidence of inflammatory bowel disease among US women. Gut 2012; 61:1686-92. [CrossRef], [PubMed], [Web of Science ®]
- 128. Jorgensen SP, Agnholt J, Glerup H, Lyhne S, Villadsen GE, Hvas CL, Bartels LE, Kelsen J, Christensen LA, Dahlerup JF. Clinical trial: vitamin D3 treatment in Crohn's disease - a randomized double-blind placebo-controlled study. Alimentary pharmacology & therapeutics 2010; 32:377-83. [CrossRef], [PubMed], [Web of Science ®]
- 129. Jantchou P, Clavel-Chapelon F, Racine A, Kvaskoff M, Carbonnel F, Boutron-Ruault MC. High residential sun exposure is associated with a low risk of incident Crohn's disease in the prospective E3N cohort. Inflamm Bowel Dis 2014; 20:75-81. [PubMed], [Web of Science ®]
- 130. Lu C, Yang J, Yu W, Li D, Xiang Z, Lin Y, Yu C. Association between 25(OH)D Level, Ultraviolet Exposure, Geographical Location, and Inflammatory Bowel Disease Activity: A Systematic Review and Meta-Analysis. PloS one 2015; 10:e0132036.
- 131. Ferenkeh-Koroma A. Systemic lupus erythematosus: nurse and patient education. Nurs Stand 2012; 26:49-57; quiz 8. [PubMed]
- 132. Walling HW, Sontheimer RD. Cutaneous lupus erythematosus: issues in diagnosis and treatment. Am J Clin Dermatol 2009; 10:365-81. [PubMed], [Web of Science ®]
- 133. Baer RL, Harber LC. Photobiology of lupus erythematosus. Archives of dermatology 1965; 92:124-8.
- 134. Walsh SJ, DeChello LM. Geographical variation in mortality from systemic lupus erythematosus in the United States. Lupus 2001; 10:637-46. [PubMed], [Web of Science ®]
- 135. Grant WB. Solar UV-B radiation is linked to the geographic variation of mortality from systemic lupus erythematosus in the USA. Lupus 2004; 13:281-2. [PubMed], [Web of Science ®]
- 136. Walsh SJ, Gilchrist A. Geographical clustering of mortality from systemic lupus erythematosus in the United States: contributions of poverty, Hispanic ethnicity and solar radiation. Lupus 2006; 15:662-70. [CrossRef], [PubMed], [Web of Science ®]
- 137. Pan Q, Li Y, Ye L, Deng Z, Li L, Feng Y, Liu W, Liu H. Geographical distribution, a risk factor for the incidence of lupus nephritis in China. BMC nephrology 2014; 15:67. [PubMed]
- 138. Yang J, Lu YW, Pan HF, Tao JH, Zou YF, Bao W, Ye DQ. Seasonal distribution of systemic lupus erythematosus activity and its correlation with climate factors. Rheumatol Int 2012; 32:2393-9. [PubMed], [Web of Science ®]
- 139. Mao S, Shen H, Zhang J. Systemic lupus erythematosus and malignancies risk. J Cancer Res Clin Oncol 2015. [Web of Science ®]
- 140. Cutillas-Marco E, Morales-Suarez-Varela M, Marquina-Vila A, Grant W. Serum 25-hydroxyvitamin D levels in patients with cutaneous lupus erythematosus in a Mediterranean region. Lupus 2010; 19:810-4. [PubMed], [Web of Science ®]
- 141. Amital H, Szekanecz Z, Szucs G, Danko K, Nagy E, Csepany T, Kiss E, Rovensky J, Tuchynova A, Kozakova D, et al. Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D? Annals of the rheumatic diseases 2010; 69:1155-7. [CrossRef], [PubMed], [Web of Science ®]
- 142. Singh A, Kamen DL. Potential benefits of vitamin D for patients with systemic lupus erythematosus. Dermato-endocrinology 2012; 4:146-51. [Taylor & Francis Online], [PubMed]
- 143. Pascher F. Vitamin, antibiotic, and gold therapy for lupus erythematosus. New York state journal of medicine 1950; 50:2448-9.
- 144. Cutillas-Marco E, Marquina-Vila A, Grant WB, Vilata-Corell JJ, Morales-Suarez-Varela MM. Vitamin D and cutaneous lupus erythematosus: effect of vitamin D replacement on disease severity. Lupus 2014; 23:615-23. [PubMed], [Web of Science ®]
- 145. Terrier B, Derian N, Schoindre Y, Chaara W, Geri G, Zahr N, Mariampillai K, Rosenzwajg M, Carpentier W, Musset L, et al. Restoration of regulatory and effector T cell balance and B cell homeostasis in systemic lupus erythematosus patients through vitamin D supplementation. Arthritis Res Ther 2012; 14:R221. [PubMed], [Web of Science ®]
- 146. Abou-Raya A, Abou-Raya S, Helmii M. The effect of vitamin D supplementation on inflammatory and hemostatic markers and disease activity in patients with systemic lupus erythematosus: a randomized placebo-controlled trial. J Rheumatol 2013; 40:265-72. [CrossRef], [PubMed], [Web of Science ®]
- 147. Acheson ED. The distribution of ulcerative colitis and regional enteritis in United States veterans with particular reference to the Jewish religion. Gut 1960; 1:291-3. [CrossRef], [PubMed], [Web of Science ®]
- 148. Kurtzke JF, Beebe GW, Norman JE, Jr Epidemiology of multiple sclerosis in U.S. veterans: 1. Race, sex, and geographic distribution. Neurology 1979; 29:1228-35. [CrossRef], [PubMed], [Web of Science ®]
- 149. van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Simmons R, Taylor BV, Butzkueven H, Kilpatrick T. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ 2003; 327:316. [CrossRef], [PubMed], [Web of Science ®]
- 150. Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Medical hypotheses 1986; 21:193-200. [CrossRef], [PubMed], [Web of Science ®]
- 151. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA : the journal of the American Medical Association 2006; 296:2832-8. [CrossRef], [PubMed], [Web of Science ®]
- 152. Mokry LE, Ross S, Ahmad OS, Forgetta V, Smith GD, Leong A, Greenwood CM, Thanassoulis G, Richards JB. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS medicine 2015; 12:e1001866. [PubMed]
- 153. Becklund BR, Severson KS, Vang SV, DeLuca HF. UV radiation suppresses experimental autoimmune encephalomyelitis independent of vitamin D production. Proceedings of the National Academy of Sciences of the United States of America 2010; 107:6418-23.
- 154. Lucas RM, Ponsonby AL, Dear K, Valery PC, Pender MP, Taylor BV, Kilpatrick TJ, Dwyer T, Coulthard A, Chapman C, et al. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology 2011; 76:540-8. [CrossRef], [PubMed], [Web of Science ®]
- 155. Knippenberg S, Damoiseaux J, Bol Y, Hupperts R, Taylor BV, Ponsonby AL, Dwyer T, Simpson S, van der Mei IA. Higher levels of reported sun exposure, and not vitamin D status, are associated with less depressive symptoms and fatigue in multiple sclerosis. Acta Neurol Scand 2014; 129:123-31. [PubMed], [Web of Science ®]
- 156. Wright HP. Vitamin D Concentrate in the Treatment of Rheumatoid Arthritis. Can Med Assoc J 1946; 55:175. [PubMed], [Web of Science ®]
- 157. Addis HS, Currie RD. Hypercalcaemia during vitamin D treatment of rheumatoid arthritis. British medical journal 1950; 1:877-9. [PubMed]
- 158. Andjelkovic Z, Vojinovic J, Pejnovic N, Popovic M, Dujic A, Mitrovic D, Pavlica L, Stefanovic D. Disease modifying and immunomodulatory effects of high dose 1 alpha (OH) D3 in rheumatoid arthritis patients. Clin Exp Rheumatol 1999; 17:453-6. [PubMed], [Web of Science ®]
- 159. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG, Iowa Women's Health S. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum 2004; 50:72-7. [CrossRef], [PubMed], [Web of Science ®]
- 160. Cutolo M, Otsa K, Laas K, Yprus M, Lehtme R, Secchi ME, Sulli A, Paolino S, Seriolo B. Circannual vitamin d serum levels and disease activity in rheumatoid arthritis: Northern versus Southern Europe. Clin Exp Rheumatol 2006; 24:702-4. [PubMed], [Web of Science ®]
- 161. Rossini M, Maddali Bongi S, La Montagna G, Minisola G, Malavolta N, Bernini L, Cacace E, Sinigaglia L, Di Munno O, Adami S. Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with disease activity and disability. Arthritis Res Ther 2010; 12:R216. [PubMed], [Web of Science ®]
- 162. Rezai MR, Balakrishnan Nair S, Cowan B, Young A, Sattar N, Finn JD, Wu FC, Cruickshank JK. Low vitamin D levels are related to left ventricular concentric remodelling in men of different ethnic groups with varying cardiovascular risk. International journal of cardiology 2012; 158:444-7. [PubMed], [Web of Science ®]
- 163. Di Franco M, Barchetta I, Iannuccelli C, Gerardi MC, Frisenda S, Ceccarelli F, Valesini G, Cavallo MG. Hypovitaminosis D in recent onset rheumatoid arthritis is predictive of reduced response to treatment and increased disease activity: a 12 month follow-up study. BMC Musculoskelet Disord 2015; 16:53. [PubMed]
- 164. Roux CH, Saraux A, Le Bihan E, Fardellone P, Guggenbuhl P, Fautrel B, Masson C, Chary-Valckenaere I, Cantagrel A, Juvin R, et al. Rheumatoid arthritis and spondyloarthropathies: geographical variations in prevalence in France. J Rheumatol 2007; 34:117-22. [PubMed], [Web of Science ®]
- 165. Costenbader KH, Chang SC, Laden F, Puett R, Karlson EW. Geographic variation in rheumatoid arthritis incidence among women in the United States. Archives of internal medicine 2008; 168:1664-70. [PubMed]
- 166. Vieira VM, Hart JE, Webster TF, Weinberg J, Puett R, Laden F, Costenbader KH, Karlson EW. Association between residences in U.S. northern latitudes and rheumatoid arthritis: A spatial analysis of the Nurses' Health Study. Environmental health perspectives 2010; 118:957-61. [CrossRef], [PubMed], [Web of Science ®]
- 167. Arkema EV, Hart JE, Bertrand KA, Laden F, Grodstein F, Rosner BA, Karlson EW, Costenbader KH. Exposure to ultraviolet-B and risk of developing rheumatoid arthritis among women in the Nurses' Health Study. Annals of the rheumatic diseases 2013; 72:506-11. [PubMed], [Web of Science ®]
- 168. Camargo CA, Jr., Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR, Kleinman K, Gillman MW. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. The American journal of clinical nutrition 2007; 85:788-95. [PubMed], [Web of Science ®]
- 169. Leffell DJ, Brash DE. Sunlight and skin cancer. Scientific American 1996; 275:52-3, 6–9. [CrossRef], [PubMed], [Web of Science ®]
- 170. Fioletov VE, McArthur LJ, Mathews TW, Marrett L. Estimated ultraviolet exposure levels for a sufficient vitamin D status in North America. Journal of photochemistry and photobiology B, Biology 2010; 100:57-66. [CrossRef], [PubMed], [Web of Science ®]
- 171. Mullins RJ, Clark S, Camargo CA, Jr. Regional variation in epinephrine autoinjector prescriptions in Australia: more evidence for the vitamin D-anaphylaxis hypothesis. Ann Allergy Asthma Immunol 2009; 103:488-95. [CrossRef], [PubMed], [Web of Science ®]
- 172. Rudders SA, Espinola JA, Camargo CA, Jr. North-south differences in US emergency department visits for acute allergic reactions. Ann Allergy Asthma Immunol 2010; 104:413-6. [PubMed], [Web of Science ®]
- 173. Hoyos-Bachiloglu R, Morales PS, Cerda J, Talesnik E, Gonzalez G, Camargo CA, Jr., Borzutzky A. Higher latitude and lower solar radiation influence on anaphylaxis in Chilean children. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology 2014; 25:338-43. [PubMed], [Web of Science ®]
- 174. Suaini NH, Zhang Y, Vuillermin PJ, Allen KJ, Harrison LC. Immune Modulation by Vitamin D and Its Relevance to Food Allergy. Nutrients 2015; 7:6088-108. [PubMed], [Web of Science ®]
- 175. Lynch WS, Martin JS, Roenigk HH, Jr. Clinical results of photochemotherapy. The Cleveland Clinic experience. Cutis 1977; 20:477-80. [PubMed], [Web of Science ®]
- 176. Hannuksela M, Karvonen J, Husa M, Jokela R, Katajamaki L, Leppisaari M. Ultraviolet light therapy in atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1985; 114:137-9.
- 177. Weiland SK, Husing A, Strachan DP, Rzehak P, Pearce N, Group IPOS. Climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children. Occupational and environmental medicine 2004; 61:609-15. [CrossRef], [PubMed], [Web of Science ®]
- 178. Patrizi A, Savoia F, Giacomini F, Tabanelli M, Gurioli C. The effect of summer holidays and sun exposure on atopic dermatitis. G Ital Dermatol Venereol 2009; 144:463-6. [PubMed], [Web of Science ®]
- 179. Osborne NJ, Ukoumunne OC, Wake M, Allen KJ. Prevalence of eczema and food allergy is associated with latitude in Australia. J Allergy Clin Immunol 2012; 129:865-7. [CrossRef], [PubMed], [Web of Science ®]
- 180. Silverberg JI, Hanifin J, Simpson EL. Climatic factors are associated with childhood eczema prevalence in the United States. The Journal of investigative dermatology 2013; 133:1752-9. [CrossRef], [PubMed], [Web of Science ®]
- 181. Javanbakht MH, Keshavarz SA, Djalali M, Siassi F, Eshraghian MR, Firooz A, Seirafi H, Ehsani AH, Chamari M, Mirshafiey A. Randomized controlled trial using vitamins E and D supplementation in atopic dermatitis. J Dermatolog Treat 2011; 22:144-50. [Taylor & Francis Online], [PubMed], [Web of Science ®]
- 182. Amestejani M, Salehi BS, Vasigh M, Sobhkhiz A, Karami M, Alinia H, Kamrava SK, Shamspour N, Ghalehbaghi B, Behzadi AH. Vitamin D supplementation in the treatment of atopic dermatitis: a clinical trial study. J Drugs Dermatol 2012; 11:327-30. [PubMed], [Web of Science ®]
- 183. Hata TR, Audish D, Kotol P, Coda A, Kabigting F, Miller J, Alexandrescu D, Boguniewicz M, Taylor P, Aertker L, et al. A randomized controlled double-blind investigation of the effects of vitamin D dietary supplementation in subjects with atopic dermatitis. Journal of the European Academy of Dermatology and Venereology : JEADV 2014; 28:781-9. [PubMed], [Web of Science ®]
- 184. Cannell JJ. Paracetamol, oxidative stress, vitamin D and autism spectrum disorders. International journal of epidemiology 2014; 43:974-5. [PubMed], [Web of Science ®]
- 185. Palmer DJ. Vitamin D and the Development of Atopic Eczema. J Clin Med 2015; 4:1036-50. [PubMed]
- 186. Jones DS, Podolsky SH, Greene JA. The burden of disease and the changing task of medicine. The New England journal of medicine 2012; 366:2333-8. [CrossRef], [PubMed], [Web of Science ®]
- 187. Baiz N, Dargent-Molina P, Wark JD, Souberbielle JC, Annesi-Maesano I, Group EM-CCS. Cord serum 25-hydroxyvitamin D and risk of early childhood transient wheezing and atopic dermatitis. J Allergy Clin Immunol 2014; 133:147-53. [CrossRef], [PubMed], [Web of Science ®]
- 188. Stearns V, Visvanathan K. Optimizing vitamin D concentrations for breast cancer risk reduction. Medicine 2013; 92:132-4. [PubMed], [Web of Science ®]
- 189. Grant WB, Cannell JJ. Autism prevalence in the United States with respect to solar UV-B doses: An ecological study. Dermato-endocrinology 2013; 5:159-64. [Taylor & Francis Online], [PubMed]
- 190. Bener A, Kamal M. Predict attention deficit hyperactivity disorder? Evidence -based medicine. Global journal of health science 2014; 6:47-57.
- 191. Goksugur SB, Tufan AE, Semiz M, Gunes C, Bekdas M, Tosun M, Demircioglu F. Vitamin D status in children with attention-deficit-hyperactivity disorder. Pediatrics international : official journal of the Japan Pediatric Society 2014; 56:515-9. [PubMed], [Web of Science ®]
- 192. Morales E, Julvez J, Torrent M, Ballester F, Rodriguez-Bernal CL, Andiarena A, Vegas O, Castilla AM, Rodriguez-Dehli C, Tardon A, et al. Vitamin D in Pregnancy and Attention Deficit Hyperactivity Disorder-like Symptoms in Childhood. Epidemiology 2015; 26:458-65. [PubMed], [Web of Science ®]
- 193. Burnett A, Davey CG, Wood SJ, Wilson-Ching M, Molloy C, Cheong JL, Doyle LW, Anderson PJ. Extremely preterm birth and adolescent mental health in a geographical cohort born in the 1990s. Psychol Med 2014; 44:1533-44. [CrossRef], [PubMed], [Web of Science ®]
- 194. Bodnar LM, Platt RW, Simhan HN. Early-pregnancy vitamin D deficiency and risk of preterm birth subtypes. Obstet Gynecol 2015; 125:439-47. [PubMed], [Web of Science ®]
- 195. Shang-Guan LL, Zhao YR. [Serum levels of 25-hydroxyvitamin D in children with attention deficit hyperactivity disorder]. Zhongguo Dang Dai Er Ke Za Zhi 2015; 17:837-40. [PubMed]
- 196. Patrick RP, Ames BN. Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2015; 29:2207-22. [PubMed], [Web of Science ®]
- 197. Cannell JJ. Autism and vitamin D. Medical hypotheses 2008; 70:750-9. [CrossRef], [PubMed], [Web of Science ®]
- 198. Waldman M, Nicholson S, Adilov N, Williams J. Autism prevalence and precipitation rates in California, Oregon, and Washington counties. Archives of pediatrics & adolescent medicine 2008; 162:1026-34. [PubMed]
- 199. Mostafa GA, Al-Ayadhi LY. Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. Journal of neuroinflammation 2012; 9:201. [CrossRef], [PubMed], [Web of Science ®]
- 200. Kocovska E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Research in developmental disabilities 2012; 33:1541-50. [CrossRef], [PubMed], [Web of Science ®]
- 201. Cannell JJ, Grant WB. What is the role of vitamin D in autism? Dermato-endocrinology 2013; 5:199-204. [Taylor & Francis Online], [PubMed]
- 202. Whitehouse AJ, Holt BJ, Serralha M, Holt PG, Hart PH, Kusel MM. Maternal vitamin D levels and the autism phenotype among offspring. Journal of autism and developmental disorders 2013; 43:1495-504. [PubMed], [Web of Science ®]
- 203. Cannell JJ. Autism, will vitamin D treat core symptoms? Medical hypotheses 2013; 81:195-8. [CrossRef], [PubMed], [Web of Science ®]
- 204. Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, Cannell JJ, Bjorklund G, Abdel-Reheim MK, Othman HA, El-Houfey AA, Abd El-Aziz NH, et al. Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children. Nutr Neurosci 2015. [PubMed]
- 205. Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Sconberg JL, Schmidt LC, Volk HE, Tassone F. Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study. Early Hum Dev 2015; 91:483-9. [PubMed], [Web of Science ®]
- 206. Patrick RP, Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2014; 28:2398-413. [PubMed], [Web of Science ®]
- 207. Walsh K, Cruddas M, Coggon D. Low back pain in eight areas of Britain. Journal of epidemiology and community health 1992; 46:227-30. [CrossRef], [PubMed], [Web of Science ®]
- 208. Al Faraj S,Al Mutairi K. Vitamin D deficiency and chronic low back pain in Saudi Arabia. Spine (Phila Pa 1976) 2003; 28:177-9.
- 209. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clinic proceedings 2003; 78:1463-70.
- 210. Zeng QY, Chen R, Xiao ZY, Huang SB, Liu Y, Xu JC, Chen SL, Darmawan J, Couchman KG, Wigley RD, et al. Low prevalence of knee and back pain in southeast China; the Shantou COPCORD study. J Rheumatol 2004; 31:2439-43. [PubMed], [Web of Science ®]
- 211. Hoy D, March L, Brooks P, Blyth F, Woolf A, Bain C, Williams G, Smith E, Vos T, Barendregt J, et al. The global burden of low back pain: estimates from the Global Burden of Disease 2010 study. Annals of the rheumatic diseases 2014; 73:968-74. [CrossRef], [PubMed], [Web of Science ®]
- 212. Grant WB. Overweight/obesity and vitamin D deficiency contribute to the global burden of low back pain. Annals of the rheumatic diseases 2014; 73:e48. [PubMed], [Web of Science ®]
- 213. Gendelman O, Itzhaki D, Makarov S, Bennun M, Amital H. A randomized double-blind placebo-controlled study adding high dose vitamin D to analgesic regimens in patients with musculoskeletal pain. Lupus 2015; 24:483-9. [PubMed], [Web of Science ®]
- 214. Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension 1997; 30:150-6. [CrossRef], [PubMed], [Web of Science ®]
- 215. Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC, Curhan GC. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension 2007; 49:1063-9. [CrossRef], [PubMed], [Web of Science ®]
- 216. Forman JP, Curhan GC, Taylor EN. Plasma 25-Hydroxyvitamin D Levels and Risk of Incident Hypertension Among Young Women. Hypertension 2008. [PubMed]
- 217. Ke L, Mason RS, Kariuki M, Mpofu E, Brock KE. Vitamin D status and hypertension: a review. Integr Blood Press Control 2015; 8:13-35. [PubMed]
- 218. Vimaleswaran KS, Cavadino A, Berry DJ, LifeLines Cohort Study i, Jorde R, Dieffenbach AK, Lu C, Alves AC, Heerspink HJ, Tikkanen E, et al. Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study. The lancet Diabetes & endocrinology 2014; 2:719-29. [CrossRef], [PubMed], [Web of Science ®]
- 219. Beveridge LA, Struthers AD, Khan F, Jorde R, Scragg R, Macdonald HM, Alvarez JA, Boxer RS, Dalbeni A, Gepner AD, et al. Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data. JAMA internal medicine 2015; 175:745-54. [CrossRef], [PubMed], [Web of Science ®]
- 220. Deliconstantinos G, Villiotou V, Stavrides JC. Nitric oxide and peroxynitrite released by ultraviolet B-irradiated human endothelial cells are possibly involved in skin erythema and inflammation. Exp Physiol 1996; 81:1021-33. [PubMed], [Web of Science ®]
- 221. Tonacci A, Baldus G, Corda D, Piccaluga E, Andreassi M, Cremonesi A, Guagliumi G, Picano E. Olfactory non-cancer effects of exposure to ionizing radiation in staff working in the cardiac catheterization laboratory. International journal of cardiology 2014; 171:461-3. [PubMed], [Web of Science ®]
- 222. Kurtzke JF, Goldberg ID. Parkinsonism death rates by race, sex, and geography. Neurology 1988; 38:1558-61. [PubMed], [Web of Science ®]
- 223. Lanska DJ. The geographic distribution of Parkinson's disease mortality in the United States. J Neurol Sci 1997; 150:63-70. [PubMed], [Web of Science ®]
- 224. Newmark HL, Newmark J. Vitamin D and Parkinson's disease–a hypothesis. Mov Disord 2007; 22:461-8. [CrossRef], [PubMed], [Web of Science ®]
- 225. Kenborg L, Lassen CF, Ritz B, Schernhammer ES, Hansen J, Gatto NM, Olsen JH. Outdoor work and risk for Parkinson's disease: a population-based case-control study. Occupational and environmental medicine 2011; 68:273-8. [PubMed], [Web of Science ®]
- 226. Knekt P, Kilkkinen A, Rissanen H, Marniemi J, Saaksjarvi K, Heliovaara M. Serum vitamin D and the risk of Parkinson disease. Arch Neurol 2010; 67:808-11. [PubMed]
- 227. Evatt ML, Delong MR, Khazai N, Rosen A, Triche S, Tangpricha V. Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol 2008; 65:1348-52. [CrossRef], [PubMed], [Web of Science ®]
- 228. O'Riordan JL, Bijvoet OL. Rickets before the discovery of vitamin D. Bonekey Rep 2014; 3:478. [PubMed]
- 229. Brimblecombe N, Knapp M, Murguia S, Mbeah-Bankas H, Crane S, Harris A, Evans-Lacko S, Ardino V, Iemmi V, King D. The role of youth mental health services in the treatment of young people with serious mental illness: 2-year outcomes and economic implications. Early Interv Psychiatry 2015. [PubMed]
- 230. Kato T, Ohkosi K, Suetake T, Tabata N, Tagami H. Acral lentiginous melanoma of the palm. Clin Exp Dermatol 1996; 21:388-9. [PubMed], [Web of Science ®]
- 231. Hess AF. Diet, nutrition, and infection. Acta paediatrica 1932; 13:206-24.
- 232. Evans EL. Case of Charcot's Arthropathy of the Tarsus, with Normal Kneejerks and Normal Pupil Reflexes. Proceedings of the Royal Society of Medicine 1922; 15:8-9. [PubMed]
- 233. Mills CA. Eskimo Sexual Functions. Science 1939; 89:11-2. [PubMed]
- 234. Zaloga GP, Chernow B. The multifactorial basis for hypocalcemia during sepsis. Studies of the parathyroid hormone-vitamin D axis. Annals of internal medicine 1987; 107:36-41. [PubMed], [Web of Science ®]
- 235. Colston KW, Berger U, Coombes RC. Possible role for vitamin D in controlling breast cancer cell proliferation. Lancet 1989; 1:188-91. [CrossRef], [PubMed], [Web of Science ®]
- 236. Lowe LC, Guy M, Mansi JL, Peckitt C, Bliss J, Wilson RG, Colston KW. Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer 2005; 41:1164-9. [CrossRef], [PubMed], [Web of Science ®]
- 237. Lefkowitz ES, Garland CF. Sunlight, vitamin D, and ovarian cancer mortality rates in US women. International journal of epidemiology 1994; 23:1133-6. [CrossRef], [PubMed], [Web of Science ®]
- 238. Toriola AT, Surcel HM, Calypse A, Grankvist K, Luostarinen T, Lukanova A, Pukkala E, Lehtinen M. Independent and joint effects of serum 25-hydroxyvitamin D and calcium on ovarian cancer risk: a prospective nested case-control study. Eur J Cancer 2010; 46:2799-805. [CrossRef], [PubMed], [Web of Science ®]
- 239. Corder EH, Guess HA, Hulka BS, Friedman GD, Sadler M, Vollmer RT, Lobaugh B, Drezner MK, Vogelman JH, Orentreich N. Vitamin D and prostate cancer: a prediagnostic study with stored sera. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 1993; 2:467-72. [PubMed], [Web of Science ®]
- 240. Bentham G, Aase A. Incidence of malignant melanoma of the skin in Norway, 1955–1989: associations with solar ultraviolet radiation, income and holidays abroad. International journal of epidemiology 1996; 25:1132-8. [CrossRef], [PubMed], [Web of Science ®]
- 241. Hartge P, Devesa SS, Grauman D, Fears TR, Fraumeni JF, Jr. Non-Hodgkin's lymphoma and sunlight. Journal of the National Cancer Institute 1996; 88:298-300. [CrossRef], [PubMed], [Web of Science ®]
- 242. McDermott MF, Ramachandran A, Ogunkolade BW, Aganna E, Curtis D, Boucher BJ, Snehalatha C, Hitman GA. Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians. Diabetologia 1997; 40:971-5. [PubMed], [Web of Science ®]
- 243. Muller K, Kriegbaum NJ, Baslund B, Sorensen OH, Thymann M, Bentzen K. Vitamin D3 metabolism in patients with rheumatic diseases: low serum levels of 25-hydroxyvitamin D3 in patients with systemic lupus erythematosus. Clinical rheumatology 1995; 14:397-400. [PubMed], [Web of Science ®]
- 244. Craelius W. Comparative epidemiology of multiple sclerosis and dental caries. Journal of epidemiology and community health 1978; 32:155-65. [CrossRef], [PubMed], [Web of Science ®]
- 245. Grant WB. The geographic variation in the prevalence of attention-deficit/hyperactivity disorder in the United States is likely due to geographic variations of solar ultraviolet B doses and race. Biological psychiatry 2014; 75:e1. [CrossRef], [PubMed], [Web of Science ®]
- 246. Stegeman I, Bossuyt PM, Yu T, Boyd C, Puhan MA. Aspirin for Primary Prevention of Cardiovascular Disease and Cancer. A Benefit and Harm Analysis. PloS one 2015; 10:e0127194.
- 247. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature 2015; 526:343-50. [PubMed], [Web of Science ®]
- 248. Fumagalli M, Moltke I, Grarup N, Racimo F, Bjerregaard P, Jorgensen ME, Korneliussen TS, Gerbault P, Skotte L, Linneberg A, et al. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science 2015; 349:1343-7. [PubMed], [Web of Science ®]
- 249. Schwartz S. The fallacy of the ecological fallacy: the potential misuse of a concept and the consequences. American journal of public health 1994; 84:819-24. [CrossRef], [PubMed], [Web of Science ®]
- 250. Diez-Roux AV. Bringing context back into epidemiology: variables and fallacies in multilevel analysis. American journal of public health 1998; 88:216-22. [CrossRef], [PubMed], [Web of Science ®]
- 251. Greenland S. Ecologic versus individual-level sources of bias in ecologic estimates of contextual health effects. International journal of epidemiology 2001; 30:1343-50. [CrossRef], [PubMed], [Web of Science ®]
- 252. Adams SV, Newcomb PA, Burnett-Hartman AN, White E, Mandelson MT, Potter JD. Circulating 25-hydroxyvitamin-D and risk of colorectal adenomas and hyperplastic polyps. Nutrition and cancer 2011; 63:319-26. [Taylor & Francis Online], [PubMed], [Web of Science ®]
- 253. Hart PH. Vitamin D supplementation, moderate sun exposure, and control of immune diseases. Discov Med 2012; 13:397-404. [PubMed]
- 254. Juzeniene A, Moan J. Beneficial effects of UV radiation other than via vitamin D production. Dermato-endocrinology 2012; 4:109-17. [Taylor & Francis Online], [PubMed]
- 255. Tan KH, Simonella L, Wee HL, Roellin A, Lim YW, Lim WY, Chia KS, Hartman M, Cook AR. Quantifying the natural history of breast cancer. British journal of cancer 2013; 109:2035-43. [PubMed], [Web of Science ®]
- 256. Breuer J, Schwab N, Schneider-Hohendorf T, Marziniak M, Mohan H, Bhatia U, Gross CC, Clausen BE, Weishaupt C, Luger TA, et al. Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. Ann Neurol 2014; 75:739-58. [CrossRef], [PubMed], [Web of Science ®]
- 257. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiology and infection 2006; 134:1129-40. [CrossRef], [PubMed], [Web of Science ®]
- 258. Weyland PG, Grant WB, Howie-Esquivel J. Does sufficient evidence exist to support a causal association between vitamin D status and cardiovascular disease risk? An assessment using Hill's criteria for causality. Nutrients 2014; 6:3403-30. [PubMed], [Web of Science ®]
- 259. Shaman J, Jeon CY, Giovannucci E, Lipsitch M. Shortcomings of vitamin D-based model simulations of seasonal influenza. PloS one 2011; 6:e20743. [PubMed]
- 260. Hu Z, Rao KR. Particulate air pollution and chronic ischemic heart disease in the eastern United States: a county level ecological study using satellite aerosol data. Environ Health 2009; 8:26. [CrossRef], [PubMed], [Web of Science ®]
- 261. Hu Z. Spatial analysis of MODIS aerosol optical depth, PM2.5, and chronic coronary heart disease. International journal of health geographics 2009; 8:27. [CrossRef], [PubMed], [Web of Science ®]
- 262. Wang L, Song Y, Manson JE, Pilz S, Marz W, Michaelsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circulation Cardiovascular quality and outcomes 2012; 5:819-29. [CrossRef], [PubMed], [Web of Science ®]
- 263. Kulshreshtha A, Vaccarino V, Judd SE, Howard VJ, McClellan WM, Muntner P, Hong Y, Safford MM, Goyal A, Cushman M. Life's Simple 7 and risk of incident stroke: the reasons for geographic and racial differences in stroke study. Stroke; a journal of cerebral circulation 2013; 44:1909-14. [PubMed], [Web of Science ®]
- 264. Toriola AT, Colditz GA. Trends in breast cancer incidence and mortality in the United States: implications for prevention. Breast cancer research and treatment 2013; 138:665-73. [CrossRef], [PubMed], [Web of Science ®]
- 265. Ginde AA, Liu MC, Camargo CA, Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004. Archives of internal medicine 2009; 169:626-32. [CrossRef], [PubMed], [Web of Science ®]
- 266. Kristal AR. Are clinical trials the “gold standard” for cancer prevention research? Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2008; 17:3289-91.
- 267. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364:2021-9. [CrossRef], [PubMed], [Web of Science ®]
- 268. Hill AB. The Environment and Disease: Association or Causation? Proceedings of the Royal Society of Medicine 1965; 58:295-300. [PubMed]
- 269. Potischman N, Weed DL. Causal criteria in nutritional epidemiology. The American journal of clinical nutrition 1999; 69:1309S-14S. [PubMed], [Web of Science ®]
- 270. Grant WB. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer?: An examination using Hill's criteria for causality. Dermato-endocrinology 2009; 1:17-24. [Taylor & Francis Online], [PubMed]
- 271. Mohr SB, Gorham ED, Alcaraz JE, Kane CI, Macera CA, Parsons JK, Wingard DL, Garland CF. Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria? Dermato-endocrinology 2012; 4:152-7. [Taylor & Francis Online], [PubMed]
- 272. Hanwell HE, Banwell B. Assessment of evidence for a protective role of vitamin D in multiple sclerosis. Biochimica et biophysica acta 2011; 1812:202-12. [CrossRef], [PubMed], [Web of Science ®]
- 273. Grant WB, Boucher BJ. Are Hill's criteria for causality satisfied for vitamin D and periodontal disease? Dermato-endocrinology 2010; 2:30-6. [Taylor & Francis Online], [PubMed]
- 274. Farman J, Chen CK, Schulze G, Teitcher J. Solid and papillary epithelial pancreatic neoplasm: an unusual tumor. Gastrointest Radiol 1987; 12:31-4. [PubMed]
- 275. Randel WJ, Stolarski RS, Cunnold DM, Logan JA, Newchurch MJ, Zawodny JM. Trends in the vertical distribution of ozone. Science 1999; 285:1689-92. [CrossRef], [PubMed], [Web of Science ®]
- 276. Molina M, Ortega G, Salinas F, Bermudo J, Morales A, Carmena R. [Weber-Christian panniculitis with articular and hematological involvement].Med Clin (Barc) 1983; 80:130-2. [PubMed], [Web of Science ®]
- 277. Anderson JG, Jay SJ, Perry J, Anderson MM. Physician use of HIS impacts quality of care. US Healthc 1989; 6:41-2, 6. [PubMed]
- 278. Molina MJ, Tso TL, Molina LT, Wang FC. Antarctic stratospheric chemistry of chlorine nitrate, hydrogen chloride, and ice: release of active chlorine. Science 1987; 238:1253-7. [CrossRef], [PubMed], [Web of Science ®]
- 279. Solomon S, Portmann RW, Thompson DW. Contrasts between Antarctic and Arctic ozone depletion. Proceedings of the National Academy of Sciences of the United States of America 2007; 104:445-9. [PubMed], [Web of Science ®]
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