Vitamin D and Mortality: A Mendelian Randomization Study

Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Clinical Chemistry (Impact Factor: 7.91). 01/2013; 59(5). DOI: 10.1373/clinchem.2012.193185
Source: PubMed


Decreased circulating 25-hydroxy-vitamin D (25-OH-vitamin D) concentrations have been associated with mortality rates, but it is unclear whether this association is causal. We performed a Mendelian randomization study and analyzed whether 3 common single-nucleotide polymorphisms (SNPs) associated with 25-OH-vitamin D concentrations are causal for mortality rates.

Genotypes of SNPs in the group-specific component gene (GC, rs2282679), 7-dehydrocholesterol reductase gene (DHCR7, rs12785878), and cytochrome P450 IIR-1 gene (CYP2R1, rs10741657) were determined in a prospective cohort study of 3316 male and female participants [mean age 62.6 (10.6) years] scheduled for coronary angiography between 1997 and 2000. 25-OH-vitamin D concentrations were determined by RIA. The main outcome measures were all-cause deaths, cardiovascular deaths, and noncardiovascular deaths.

In a linear regression model adjusting for month of blood sampling, age, and sex, vitamin D concentrations were predicted by GC genotype (P < 0.001), CYP2R1 genotype (P = 0.068), and DHCR7 genotype (P < 0.001), with a coefficient of determination (r(2)) of 0.175. During a median follow-up time of 9.9 years, 955 persons (30.0%) died, including 619 deaths from cardiovascular causes. In a multivariate Cox regression adjusted for classical risk factors, GC, CYP2R1, and DHCR7 genotypes were not associated with all-cause mortality, cardiovascular mortality, or noncardiovascular mortality.

Genetic variants associated with 25-OH-vitamin D concentrations do not predict mortality. This suggests that low 25-OH-vitamin D concentrations are associated with, but unlikely to be causal for, higher mortality rates.

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    • "for subjects in the highest quartile of a genotype score based on rs2298850 (GC), rs10741657 (CYP2R1), rs3794060 (DHCR7/NADSYN1), and rs6013897 (CYP24A1). Also, no association between genetic vitamin D status determinants (rs2282679, rs12785878, and rs10741657) and CVD mortality was observed in a population of 3316 subjects scheduled for coronary angiography comprising 619 later cases of fatal CVD [41]. Still, we cannot rule out the detection of modest associations between SNPs related to vitamin D status and MI or stroke in larger consortia, as a post hoc calculation revealed that we only had the power of 0.62, 0.46 and 0.42 to detect HRs of 1.3 for incident overall CVD, MI, and stroke, respectively, between extreme categories of our SNP score. "
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    ABSTRACT: Circulating 25-hydroxyvitamin D (25(OH)D) has been associated with cardiovascular disease (CVD) risk in observational studies. Also, SNPs to explain variation in 25(OH)D have been identified by genome-wide association studies. Detection of direct associations between SNPs that significantly affect 25(OH)D and CVD risk would indicate a causal role of vitamin D, as reverse causation could be excluded and confounding could be better controlled. Thus, a combined analysis of candidate SNPs in relation to circulating 25(OH)D and CVD risk was carried out. A case-cohort study within the EPIC-Germany study was conducted comprising a randomly drawn subcohort of 2,132 subjects (57.9% women, mean age: 50.6 years) and incident cases of myocardial infarction (n=559) and stroke (n=471) that occurred during a mean follow-up duration of 7.6 years. 25(OH)D concentrations were measured by LC-MS/MS in baseline plasma samples. Additionally, eight candidate SNPs were assayed. Associations between 25(OH)D, SNPs and the risks of myocardial infarction and stroke were assessed by multivariable regression analyses. Mean 25(OH)D level was 47.2 nmol/L in the subcohort. Four SNPs were associated with 25(OH)D (p<0.05). In subjects with 25(OH)D levels <25 nmol/L, the risks of CVD as composite endpoint (Hazard Ratio: 1.53, 95% confidence interval: 1.12-2.09), myocardial infarction, and stroke were significantly increased compared to subjects with levels ≥50 nmol/L, while no significant linear associations were observed. A SNP score was not related to the risks of total CVD (Hazard Ratio: 1.0, 95% confidence interval: 0.71-1.42), myocardial infarction, or stroke. The same was true concerning single SNPs. Given the lack of association between SNPs and the risks of stroke and myocardial infarction, the present findings do not point to a major causal role of vitamin D in the development of these diseases. However, a detection of modest associations between genetic markers and CVD risk in larger consortia cannot be ruled out.
    Full-text · Article · Jul 2013 · PLoS ONE
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    Full-text · Article · Jun 2013 · Hawai'i journal of medicine & public health : a journal of Asia Pacific Medicine & Public Health
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    ABSTRACT: Few interventional studies have reported a positive effect of native vitamin D supplementation on intermediary parameters of insulin resistance, of cardiovascular risk and on major cardiovascular events and mortality.
    No preview · Article · Sep 2013 · La Presse Médicale
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