Effect of Genetically Low 25-Hydroxyvitamin D on Mortality Risk: Mendelian Randomization Analysis in 3 Large European Cohorts
Nutrients 2019, 11(1), 74; https://doi.org/10.3390/nu11010074
Mortality starts with:
The Meta-analysis of Mortality and Vitamin D are listed here:
- Deaths from many types of Cancer associated with low vitamin D- review of meta-analyses Sept 2020
- People supplemented with Vitamin D had 13 percent fewer Cancer deaths – Meta-analysis of RCT June 2019
- Cancer with low Vitamin D increases Mortality by 13 percent – meta-analysis Feb 2019
- Decreased Vitamin D is associated with dying sooner (70 studies) – meta-analysis Jan 2019
- Prostate Cancer death 40 percent less likely if 40 ng level of vitamin D – Meta-analysis Oct 2018
- Review of meta-analyses of non-skeletal benefits of vitamin D (Mortality, RTI, etc) – July 2017
- Chronic Kidney Disease mortality is 60 percent less likely if good vitamin D – meta-analysis July 2017
- Lung Cancer death 60 percent less likely if high level of vitamin D – 2 meta-analysis 2017
- Breast Cancer Mortality reduced 60 percent if more than 60 ng of Vitamin D – meta-analysis June 2017
- Cardiovascular deaths 12 percent less likely if have 10 ng more vitamin D – meta-analysis March 2017
- ICU patients 30 percent less likely to die if have enough vitamin D – meta-analysis Nov 2016
- Less likely to die if have enough vitamin D - Meta-analysis June 2014
- Cancer survival 4 percent more likely with just a little more vitamin D (4 ng) - meta-analysis July 2014
- Death due to breast cancer reduced 40 percent if high vitamin D – meta-analysis April 2014
- Vitamin D reduces risk of cause specific death, unless it is D2 – meta-analysis BMJ April 2014
- More survive Breast Cancer if more vitamin D – 2X fewer deaths with just 30 ng -meta-analysis March 2014
- Colorectal and Breast Cancer – Vitamin D is associated with fewer deaths – meta-analysis Feb 2014
- Death of women from cancer 24 percent less likely if 20 ng more vitamin D – meta-analysis Sept 2013
- Chance of dying increases by 25 percent in seniors if low vitamin D – Meta-analysis July 2013
- Breast Cancer survival 2X more likely if vitamin D sufficient – meta-analysis May 2013
- Vitamin D with Calcium reduces mortality by 7 percent – meta-analysis May 2012
- Death rate reduced 8 percent for 8 nanogram more vitamin D – meta-analysis Feb 2012
- 40 ng Vitamin D perhaps optimal for reduced mortality – Meta-analysis Jan 2012
- Vitamin D3 but not D2 reduces mortality – meta-analysis July 2011
- Vitamin D and mortality a meta-analysis of RCT - 2008
Items in both categories Mortality and Genetics are listed here:
- Vitamin D appears to keep telomeres long (longer life) – Jan 2021
- Live longer if have more than 40 ng of Vitamin D (gene analysis of 10,500 people) – Jan 2019
- Telomeres in boys were 2.5% longer if 9 ng higher vitamin D – July 2018
- 5.8 X more likely to die in 15 year followup if low vitamin D and poor methylation – July 2018
- Increased mortality associated with low vitamin D genes – Nov 2014
Note: This study ignored 5 additional genes which limit the Vitamin D in the blood from getting to the tissues. Example: The risk of 40 diseases at least double with poor Vitamin D Receptor as of July 2019
Genetics category listing contains the following
396 articles in Vitamin D Receptor 145 articles in Vitamin D Binding Protein = GC 36 articles in CYP27B1
- Topical Vitamin D
- Nanoemulsion Vitamin D may be a substantially better form
- Getting Vitamin D into your body
Vitamin D blood test misses a lot
- Snapshot of the literature by VitaminDWiki as of early 2019
- Vitamin D from coming from tissues (vs blood) was speculated to be 50% in 2014, and by 2017 was speculated to be 90%
- Note: Good blood test results (> 40 ng) does not mean that a good amount of Vitamin D actually gets to cells
- A Vitamin D test in cells rather than blood was feasible (2017 personal communication)
- Commercially available 2019
- However test results would vary in each tissue due to multiple genes
- Good clues that Vitamin D is being restricted from getting to the cells
1) A vitamin D-related health problem runs in the family
- especially if it is one of 51+ diseases related to Vitamin D Receptor
2) Slightly increasing Vitamin D show benefits (even if conventional Vitamin D test shows an increase)
3) Vitamin D Receptor test (<$30) scores are difficult to understand in 2016
- easier to understand the VDR 23andMe test results analyzed by FoundMyFitness in 2018
4) Back Pain
- probably want at least 2 clues before taking adding vitamin D, Omega-3, Magnesium, Resveratrol, etc
- The founder of VitaminDWiki took action with clues #3&4
Download the PDF from VitaminDWiki
Figure 1. Mortality rate (log-scale) for 10 years from all causes by level of standardized 25-hydroxyvitamin D.
A rug and density plot are superimposed to demonstrate where most of the 25(OH)D measurements lie.
Fitted associations are shown as linear (green line), log-linear (black line), and spline (broken line)
Authors Thor Aspelund 1,2, Martin R. Grübler 3,4,5, Albert V. Smith 1,2, Elias F. Gudmundsson 1, Martin Keppel 6, Mary Frances Cotch 7, Tamara B. Harris 8, Rolf Jorde 9, Guri Grimnes 9, Ragnar Joakimsen 9, Henrik Schirmer 10, Tom Wilsgaard 11, Ellisiv B. Mathiesen 12,13, Inger Njølstad 11, Maja-Lisa Løchen 11, Winfried März 14,15,16, Marcus E. Kleber 14,17, Andreas Tomaschitz 4,18,19, Diana Grove-Laugesen 20, Lars Rejnmark 20, Karin M. A. Swart 21, Ingeborg A. Brouwer 22, Paul Lips 23, Natasja M. van Schoor 21, Christopher T. Sempos 24, Ramón A. Durazo-Arvizu 25, Zuzana Škrabáková 26, Kirsten G. Dowling 26, Kevin D. Cashman 26,27, Mairead Kiely 26,28, Stefan Pilz 3,21, Vilmundur Gudnason 1,2 and Gudny Eiriksdottir 1,*
(This article belongs to the Special Issue Nutrition Intake and Skin Health: Vitamin D and beyond) 7 papers as of Nov 2019
The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program.
Most relevant single nucleotide polymorphisms of the genes
- CYP2R1 (rs12794714, rs10741657) and
- DHCR7/NADSYN1 (rs12785878, rs11234027),
were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15–1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80–2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores.
In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision
In conclusion, the results of this MR study may argue in favor of a causal relationship between vitamin D deficiency and increased all-cause mortality in a combined sample from three European cohort studies. These data support a previous Danish MR study with similar effects size. It is also in line with the dose-response seen in observational epidemiological studies as well as meta-analyses of vitamin D RCTs, which suggest that low 25(OH)D levels may be detrimental for survival. These findings on vitamin D and mortality deserve consideration in the public health discussion regarding the value, design, and implementation of innovative approaches to improve the vitamin D status of the general population.
Live longer if have more than 40 ng of Vitamin D (gene analysis of 10,500 people) – Jan 2019
- Pludowski, P.; Holick, M.F.; Pilz, S.; Wagner, C.L.; Hollis, B.W.; Grant, W.B.; Shoenfeld, Y.; Lerchbaum, E.; Llewellyn, D.J.; Kienreich, K.; et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence. Autoimmun. Rev. 2013,12, 976-989.
- Autier, P.; Boniol, M.; Pizot, C.; Mullie, P. Vitamin D status and ill health: A systematic review. Lancet Diabetes Endocrinol. 2014,2, 76-89.
- Kestenbaum, B.; Katz, R.; de Boer, I.; Hoofnagle, A.; Sarnak, M.J.; Shlipak, M.G.; Jenny, N.S.; Siscovick, D.S. Vitamin D, parathyroid hormone, and cardiovascular events among older adults. J. Am. Coll. Cardiol. 2011, 58,1433-1441.
- Schottker, B.; Jorde, R.; Peasey, A.; Thorand, B.; Jansen, E.H.; Groot, L.; Streppel, M.; Gardiner, J.; Ordonez-Mena, J.M.; Perna, L.; et al. Vitamin D and mortality: Meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States. BMJ 2014, 348, g3656.
- Daraghmeh, A.H.; Bertoia, M.L.; Al-Qadi, M.O.; Abdulbaki, A.M.; Roberts, M.B.; Eaton, C.B. Evidence for the vitamin D hypothesis: The NHANES III extended mortality follow-up. Atherosclerosis 2016, 255, 96-101.
- Garland, C.F.; Kim, J.J.; Mohr, S.B.; Gorham, E.D.; Grant, W.B.; Giovannucci, E.L.; Baggerly, L.; Hofflich, H.; Ramsdell, J.W.; Zeng, K.; et al. Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am. J. Public Health 2014,104, e43-e50.
- Grober, U.; Reichrath, J.; Holick, M.F. Live longer with vitamin D? Nutrients 2015, 7,1871-1880.
- Gaksch, M.; Jorde, R.; Grimnes, G.; Joakimsen, R.; Schirmer, H.; Wilsgaard, T.; Mathiesen, E.B.; Njolstad, I.; Lochen, M.L.; Marz, W.; et al. Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium. PLoS ONE 2017,12, e0170791.
- Zhu, K.; Knuiman, M.; Divitini, M.; Hung, J.; Lim, E.M.; Cooke, B.R.; Walsh, J.P. Serum 25-hydroxyvitamin D as a predictor of mortality and cardiovascular events: A 20-year study of a community-based cohort. Clin. Endocrinol. 2017.
- Bjelakovic, G.; Gluud, L.L.; Nikolova, D.; Whitfield, K.; Wetterslev, J.; Simonetti, R.G.; Bjelakovic, M.; Gluud, C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst. Rev. 2014, CD007470.
- Rejnmark, L.; Avenell, A.; Masud, T.; Anderson, F.; Meyer, H.E.; Sanders, K.M.; Salovaara, K.; Cooper, C.; Smith, H.E.; Jacobs, E.T.; et al. Vitamin D with calcium reduces mortality: Patient level pooled analysis of 70,528 patients from eight major vitamin D trials. J. Clin. Endocrinol. Metab. 2012, 97, 2670-2681.
- Bolland, M.J.; Grey, A.; Gamble, G.D.; Reid, I.R. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: A trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014, 2, 307-320.
- Chowdhury, R.; Kunutsor, S.; Vitezova, A.; Oliver-Williams, C.; Chowdhury, S.; Kiefte-de-Jong, J.C.; Khan, H.; Baena, C.P.; Prabhakaran, D.; Hoshen, M.B.; 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.
- Cashman, K.D.; Dowling, K.G.; Skrabakova, Z.; Gonzalez-Gross, M.; Valtuena, J.; De Henauw, S.; Moreno, L.; Damsgaard, C.T.; Michaelsen, K.F.; Molgaard, C.; et al. Vitamin D deficiency in Europe: Pandemic? Am. J. Clin. Nutr. 2016,103,1033-1044.
- Burgess, S.; Thompson, S.G. Mendelian Randomization: Methods for Using Genetic Variants in Causal Estimation; Chapman and Hall/CRC: New York, NY, USA, 2015.
- Afzal, S.; Brondum-Jacobsen, P.; Bojesen, S.E.; Nordestgaard, B.G. Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts. BMJ 2014, 349, g6330.
- Welsh, P.; Sattar, N. Vitamin D genes and mortality. BMJ 2014, 349, g6599.
- Harris, T.B.; Launer, L.J.; Eiriksdottir, G.; Kjartansson, O.; Jonsson, P.V.; Sigurdsson, G.; Thorgeirsson, G.; Aspelund, T.; Garcia, M.E.; Cotch, M.F.; et al. Age, Gene/Environment Susceptibility-Reykjavik Study: Multidisciplinary applied phenomics. Am. J. Epidemiol. 2007,165,1076-1087.
- Winkelmann, B.R.; Marz, W.; Boehm, B.O.; Zotz, R.; Hager, J.; Hellstern, P.; Senges, J.; Group, L.S. Rationale and design of the LURIC study—A resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics 2001,2, S1-S73.
- Jorde, R.; Schirmer, H.; Wilsgaard, T.; Joakimsen, R.M.; Mathiesen, E.B.; Njolstad, I.; Lochen, M.L.; Figenschau, Y.; Berg, J.P.; Svartberg, J.; et al. Polymorphisms related to the serum 25-hydroxyvitamin D level and risk of myocardial infarction, diabetes, cancer and mortality. The Tromso Study. PLoS ONE 2012, 7, e37295.
- Wang, T.J.; Zhang, F.; Richards, J.B.; Kestenbaum, B.; van Meurs, J.B.; Berry, D.; Kiel, D.P.; Streeten, E.A.; Ohlsson, C.; Koller, D.L.; et al. Common genetic determinants of vitamin D insufficiency: A genome-wide association study. Lancet 2010, 376,180-188.
- Dastani, Z.; Berger, C.; Langsetmo, L.; Fu, L.; Wong, B.Y.; Malik, S.; Goltzman, D.; Cole, D.E.; Richards, J.B. In healthy adults, biological activity of vitamin D, as assessed by serum PTH, is largely independent of DBP concentrations. J. Bone Miner. Res. 2014,29,494-499.
- Otterbein, L.R.; Cosio, C.; Graceffa, P.; Dominguez, R. Crystal structures of the vitamin D-binding protein and its complex with actin: Structural basis of the actin-scavenger system. Proc. Natl. Acad. Sci. USA 2002, 99, 8003-8008.
- Durazo-Arvizu, R.A.; Tian, L.; Brooks, S.P.J.; Sarafin, K.; Cashman, K.D.; Kiely, M.; Merkel, J.; Myers, G.L.; Coates, P.M.; Sempos, C.T. The Vitamin D Standardization Program (VDSP) Manual for Retrospective Laboratory Standardization of Serum 25-Hydroxyvitamin D Data. J. AOAC Int. 2017, 100, 1234-1243.
- Berry, D.J.; Vimaleswaran, K.S.; Whittaker, J.C.; Hingorani, A.D.; Hypponen, E. Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D. PLoS ONE 2012, 7, e37465.
- Ahn, J.; Yu, K.; Stolzenberg-Solomon, R.; Simon, K.C.; McCullough, M.L.; Gallicchio, L.; Jacobs, E.J.; Ascherio, A.; Helzlsouer, K.; Jacobs, K.B.; et al. Genome-wide association study of circulating vitamin D levels. Hum. Mol. Genet. 2010,19, 2739-2745.
- Palmer, T.M.; Sterne, J.A.; Harbord, R.M.; Lawlor, D.A.; Sheehan, N.A.; Meng, S.; Granell, R.; Smith, G.D.; Didelez, V. Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses. Am. J. Epidemiol. 2011,173,1392-1403.
- Fieller, E.C. Some Problems in Interval Estimation. J. R. Stat. Soc. Ser. B (Methodol.) 1954, 16, 175-185.
- Ross, A.C.; Manson, J.E.; Abrams, S.A.; Aloia, J.F.; Brannon, P.M.; Clinton, S.K.; Durazo-Arvizu, R.A.; Gallagher, J.C.; Gallo, R.L.; Jones, G.; et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J. Clin. Endocrinol. Metab. 2011, 96, 53-58.
- Pierce, B.L.; Burgess, S. Efficient design for Mendelian randomization studies: Subsample and 2-sample instrumental variable estimators. Am. J. Epidemiol. 2013,178,1177-1184.
- Jiang, X.; O'Reilly, P.F.; Aschard, H.; Hsu, Y.H.; Richards, J.B.; Dupuis, J.; Ingelsson, E.; Karasik, D.; Pilz, S.; Berry, D.; et al. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat. Commun. 2018, 9, 260.
- Li, S.S.; Gao, L.H.; Zhang, X.Y.; He, J.W.; Fu, W.Z.; Liu, Y.J.; Hu, Y.Q.; Zhang, Z.L. Genetically Low Vitamin D Levels, Bone Mineral Density, and Bone Metabolism Markers: A Mendelian Randomisation Study. Sci. Rep. 2016, 6, 33202.
- Ye, Z.; Sharp, S.J.; Burgess, S.; Scott, R.A.; Imamura, F.; InterAct, C.; Langenberg, C.; Wareham, N.J.; Forouhi, N.G. Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: A mendelian randomisation study. Lancet Diabetes Endocrinol. 2015, 3, 35-42.
- McKay, G.J.; Young, I.S.; McGinty, A.; Bentham, G.C.; Chakravarthy, U.; Rahu, M.; Seland, J.; Soubrane, G.; Tomazzoli, L.; Topouzis, F.; et al. Associations between Serum Vitamin D and Genetic Variants in Vitamin D Pathways and Age-Related Macular Degeneration in the European Eye Study. Ophthalmology 2016,124, 90-96.
- Vimaleswaran, K.S.; Cavadino, A.; Berry, D.J.; LifeLines Cohort Study Investigators; Jorde, R.; Dieffenbach, A.K.; Lu, C.; Alves, A.C.; Heerspink, H.J.; Tikkanen, E.; et al. Association of vitamin D status with arterial blood pressure and hypertension risk: A mendelian randomisation study. Lancet Diabetes Endocrinol. 2014, 2, 719-729.
- Brondum-Jacobsen, P.; Benn, M.; Afzal, S.; Nordestgaard, B.G. No evidence that genetically reduced 25-hydroxyvitamin D is associated with increased risk of ischaemic heart disease or myocardial infarction: A Mendelian randomization study. Int. J. Epidemiol. 2015, 44, 651-661.
- Afzal, S.; Brondum-Jacobsen, P.; Bojesen, S.E.; Nordestgaard, B.G. Vitamin D concentration, obesity, and risk of diabetes: A mendelian randomisation study. Lancet Diabetes Endocrinol. 2014,2, 298-306.
- Vimaleswaran, K.S.; Berry, D.J.; Lu, C.; Tikkanen, E.; Pilz, S.; Hiraki, L.T.; Cooper, J.D.; Dastani, Z.; Li, R.; Houston, D.K.; et al. Causal relationship between obesity and vitamin D status: Bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013,10, e1001383.
- Kueider, A.M.; Tanaka, T.; An, Y.; Kitner-Triolo, M.H.; Palchamy, E.; Ferrucci, L.; Thambisetty, M. State- and trait-dependent associations of vitamin-D with brain function during aging. Neurobiol. Aging 2016, 39, 38-45.
- Dimitrakopoulou, V.I.; Tsilidis, K.K.; Haycock, P.C.; Dimou, N.L.; Al-Dabhani, K.; Martin, R.M.; Lewis, S.J.; Gunter, M.J.; Mondul, A.; Shui, I.M.; et al. Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study. BMJ 2017, 359, j4761.
- Chandler, P.D.; Tobias, D.K.; Wang, L.; Smith-Warner, S.A.; Chasman, D.I.; Rose, L.; Giovannucci, E.L.; Buring, J.E.; Ridker, P.M.; Cook, N.R.; et al. Association between Vitamin D Genetic Risk Score and Cancer Risk in a Large Cohort of U.S. Women. Nutrients 2018,10, 55.
- Mokry, L.E.; Ross, S.; Morris, J.A.; Manousaki, D.; Forgetta, V.; Richards, J.B. Genetically decreased vitamin D and risk of Alzheimer disease. Neurology 2016, 87.
- Schottker, B.; Brenner, H. Vitamin D as a Resilience Factor, Helpful for Survival of Potentially Fatal Conditions: A Hypothesis Emerging from Recent Findings of the ESTHER Cohort Study and the CHANCES Consortium. Nutrients 2015, 7, 3264-3278.
- Kupferschmidt, K. Uncertain verdict as vitamin D goes on trial. Science 2012, 337,1476-1478.
- Scragg, R.; Stewart, A.W.; Waayer, D.; Lawes, C.M.M.; Toop, L.; Sluyter, J.; Murphy, J.; Khaw, K.T.; Camargo, C.A., Jr. Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study: A Randomized Clinical Trial. JAMA Cardiol. 2017, 2, 608-616.
- Lappe, J.; Watson, P.; Travers-Gustafson, D.; Recker, R.; Garland, C.; Gorham, E.; Baggerly, K.; McDonnell, S.L. Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial. JAMA 2017, 317,1234-1243.
- Zittermann, A.; Ernst, J.B.; Prokop, S.; Fuchs, U.; Dreier, J.; Kuhn, J.; Knabbe, C.; Birschmann, I.; Schulz, U.; Berthold, H.K.; et al. Effect of vitamin D on all-cause mortality in heart failure (EVITA): A 3-year randomized clinical trial with 4000 IU vitamin D daily. Eur. Heart J. 2017, 38, 2279-2286.
- Manson, J.E.; Cook, N.R.; Lee, I.M.; Christen, W.; Bassuk, S.S.; Mora, S.; Gibson, H.; Gordon, D.; Copeland, T.; D'Agostino, D.; et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N. Engl. Med. 2018.
2213 visitors, last modified 29 Nov, 2019,This page is in the following categories (# of items in each category)Mortality and D 235 Genetics 276 Vitamin D in Europe 210