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Background

Mendelian randomization MR studies use genetic variants mimicking the influence of a modifiable exposure to assess and quantify a causal association with an outcome, with an aim to avoid problems with confounding and reverse causality affecting other types of observational studies.

Aim

We evaluated genetic markers that index differences in 25-hydroxyvitamin D 25OHD as instruments for MR studies on vitamin D.

Methods and Findings

We used data from up-to 6,877 participants in the 1958 British birth cohort with information on genetic markers and 25OHD. As potential instruments, we selected 20 single nucleotide polymorphisms SNP which are located in the vitamin D metabolism pathway or affect skin pigmentation-tanning, including 4 SNPs from genome-wide association GWA meta-analyses on 25OHD. We analyzed SNP associations with 25OHD and evaluated the use of allele scores dividing genes to those affecting 25OHD synthesis DHCR7, CYP2R1 and metabolism GC, CYP24A1, CYP27B1. In addition to the GWA SNPs, only two SNPs CYP27B1, OCA2 showed evidence for association with 25OHD, with the OCA2 association abolished after lifestyle adjustment. Per allele differences varied between −0.02 and −0.08 nmol-L P≤0.02 for all, with a 6.1 nmol-L and a 10.2 nmol-L difference in 25OHD between individuals with highest compared lowest number of risk alleles in synthesis and metabolism allele scores, respectively. Individual SNPs but not allele scores showed associations with lifestyle factors. An exception was geographical region which was associated with synthesis score. Illustrative power calculations 80% power, 5% alpha suggest that approximately 80,000 participants are required to establish a causal effect of vitamin D on blood pressure using the synthesis allele score.

Conclusions

Combining SNPs into allele scores provides a more powerful instrument for MR analysis than a single SNP in isolation. Population stratification and the potential for pleiotropic effects need to be considered in MR studies on vitamin D.



Autor: Diane J. Berry , Karani S. Vimaleswaran , John C. Whittaker, Aroon D. Hingorani, Elina Hyppönen

Fuente: http://plos.srce.hr/



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