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Mendelian proof that low vitamin D (due to 3 genes) increase risk of MS by 20 percent – Nov 2016

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk

Neurol Genet 2016;2:e97; doi: 10.1212/ NXG.0000000000000097
Brooke Rhead, BS Barcellos: lbarcellos@ berkeley.edu ;Maria Baarnhielm, MD* Milena Gianfrancesco, MPH; Amanda Mok, MPH Xiaorong Shao, MA Hong Quach, BA Ling Shen, PhD Catherine Schaefer, PhD Jenny Link, PhD Alexandra Gyllenberg, PhD; Anna Karin Hedstrom, MD; Tomas Olsson, PhD Jan Hillert, PhD Ingrid Kockum, PhD M. Maria Glymour, ScD Lars Alfredsson, PhD* Lisa F. Barcellos, PhD*

VitaminDWiki Summary
  • Kaiser Permanente looked at genes of 12,000 non-hispanic whites, half of whom had MS
  • 3 genes were associated with Multiple Sclerosis, all of which are associated with Vitamin D
    • GC codes for the vitamin D–binding protein, which transports vitamin D to target tissues
    •    Note - the GC gene is invisible to normal Vitamin D tests
    • CYP2R1 converts vitamin D to its main circulating form, 25(OH)D
    • DHCR7 converts 7-dehydrocholesterol, into vitamin D3 in the skin
  • Did not notice mention of many other genes which also restrict vitamin D getting to cells

See also VitaminDWiki

The articles in both of the categories MS and Genetics are:

The articles in both of the categories MS and Vitamin D Receptor (VDRE is mentioned in PDF) are:

The articles in both of the categories MS and Vitamin D Binding Protein (GC):

Genetics category listing contains the following

266 articles in the Genetics category

see also

Vitamin D blood test misses a lot
Blood Test Misses a lot (VDW 3439)

  • 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
    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

 Download the PDF from VitaminDWiki

Objective: We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.

Methods: We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.

Results: Findings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Per- manente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64-0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76-0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76-0.94). No association was observed for age at onset or disease severity.

Conclusions: These results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors.

CI = confidence interval; EHR = electronic health record; EIMS = Epidemiological Investigation of Multiple Sclerosis; GERA = Genetic Epidemiology Research on Adult Health and Aging; GEMS = Genes and Environment in Multiple Sclerosis; GWAS = genome-wide association study; HWE = Hardy-Weinberg equilibrium; ICD-9 = International Classification of Diseases, 9th Revision; IV = instrumental variable; KPNC = Kaiser Permanente in Northern California; LD = linkage disequilibrium; MAF = minor allele frequency; MDS = multidimensional scaling; MR = mendelian randomization; MS = multiple sclerosis; MSSS = Multiple Sclerosis Severity Scores; SNP = single nucleotide polymorphism; VDRE = vitamin D response element; wGRS = weighted genetic risk score.

Multiple sclerosis (MS) is an immune-mediated, demyelinating disease that leads to a wide variety of symptoms and disability. Both genetic and environmental factors have been implicated in its etiology, including vitamin D deficiency. Observational studies have consistently shown an association of low serum 25(OH)D and increased risk of MS, but it has not been shown that low 25(OH)D is actually a cause of MS.1 The apparent beneficial effects of 25(OH)D on MS might alternately be explained by reverse causation (i.e., MS could be leading to low 25(OH)D) or by confounding by sun exposure, obesity, or some other unknown factors.

Mendelian randomization (MR), equivalently, instrumental variable (IV) analysis using a genetic instrument, is a technique that can overcome the problems of both reverse causation and confounding when assessing the causal relationship between an exposure and an outcome.2 Single nucleotide polymorphisms (SNPs) known to be associated with 25(OH)D levels, rather than measured 25 (OH)D, can be used as an IV to estimate the effect of low 25(OH)D on MS. Because SNP genotypes are determined at birth and are not likely to be influenced by potential confounding variables, the effect estimate from MR analysis should not be confounded, and reverse causation is unlikely because MS does not determine which 25(OH)D-associated SNPs are inherited (figure). We used MR analysis to estimate the causal relationship between serum 25(OH)D levels and MS susceptibility in 2 large case-control studies. We also investigated 2 clinical phenotypes for MS: age at onset and disease severity.

METHODS KPNC participants. Data were collected from members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). KPNC is an integrated health service delivery system with a membership of 3.2 million that comprises about 25—30% of the population of a 22-county service area and is the largest health care provider in northern California. Membership is largely representative of the general population in the service area; however, persons in impoverished neighborhoods are underrepresented.3
Eligible KPNC cases were defined as individuals with a diagnosis of MS by a neurologist (ICD-9 code 340.xx), age 18—69 years, and membership in KPNC at initial contact. The study was restricted to self-identified white (non-Hispanic) race/ethnicity, the population with the highest prevalence of MS. The treating neurologist was contacted for approval to contact each case as a potential MS study participant. A total of 3,293 potential MS cases were reviewed by KPNC neurologists, who approved contact with 2,823 (86%) at the time of the data freeze (August 2014). Diagnoses were validated using electronic health record (EHR) review and according to published diagnostic criteria.4 Multiple Sclerosis Severity Scores (MSSS) were calculated for each case at the time of study entry (mean disease duration = 17.7 years), as described,5 and participants were asked to recall the age of first MS symptom onset which was validated using EHR data when possible.
Controls were white (non-Hispanic) current KPNC members without a diagnosis of MS or related condition (optic neuritis, transverse myelitis, or demyelinating disease; ICD-9 codes: 340, 341.0, 341.1, 341.2, 341.20, 341.21, 341.22, 341.8, 341.9, 377.3, 377.30, 377.39, and 328.82) confirmed through EHR data. Potential study participants were contacted by email with a follow-up phone call. The participation rate was 80% for cases and 66% for controls. Genetic data were available for approximately 80% of study participants.

Additional controls were individuals of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort participating in the KPNC Research Program on Genes, Environment, and Health, which is described elsewhere (dbGaP phs000674.v2. p2) ,6,7 Respondents completed a written consent form and provided a saliva sample for DNA extraction. A total of110,266 participant samples were initially collected. Approximately 103,000 samples were successfully genotyped, and 77% of participants subsequently returned new consent forms for placement in dbGaP (NIH), resulting in a final sample size of 78,486 participants.

The rest is in the PDF

Attached files

ID Name Comment Uploaded Size Downloads
7676 Low Vitamin D causes MS - not just association.pdf PDF 2016 admin 15 Jan, 2017 22:42 398.45 Kb 416
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