Mendelian Randomization Focused Analysis of Vitamin D on the Secondary Prevention of Ischemic Stroke

Abstract

Background and Purpose: Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary prevention. Whether Vit-D protects against ischemic stroke and myocardial infarction recurrence among subjects with prior ischemic insults was unknown. Here, we dissected through Mendelian randomization any effect of Vit-D on the secondary prevention of recurrent ischemic stroke and myocardial infarction. Methods: Based on a genetic risk score for Vit-D constructed from a derivation cohort sample (n=5331, 45% Vit-D deficient, 89% genotyped) via high-throughput exome-chip screening of 12 prior genome-wide association study–identified genetic variants of Vit-D mechanistic pathways ( rs2060793 , rs4588 , and rs7041 ; F statistic, 73; P <0.001), we performed a focused analysis on prospective recurrence of myocardial infarction (MI) and ischemic stroke in an independent subsample with established ischemic disease (n=441, all with prior first ischemic event; follow-up duration, 41.6±14.3 years) under a 2-sample, individual-data, prospective Mendelian randomization approach. Results: In the ischemic disease subsample, 11.1% (n=49/441) had developed recurrent ischemic stroke or MI and 13.3% (n=58/441) had developed recurrent or de novo ischemic stroke/MI. Kaplan-Meier analyses showed that genetic risk score predicted improved event-free survival from recurrent ischemic stroke or MI (log-rank, 13.0; P =0.001). Cox regression revealed that genetic risk score independently predicted reduced risk of recurrent ischemic stroke or MI combined (hazards ratio, 0.62 [95% CI, 0.48–0.81]; P <0.001), after adjusted for potential confounders. Mendelian randomization supported that Vit-D is causally protective against the primary end points of recurrent ischemic stroke or MI (Wald estimate: odds ratio, 0.55 [95% CI, 0.35–0.81]) and any recurrent or de novo ischemic stroke/MI (odds ratio, 0.64 [95% CI, 0.42–0.91]) and recurrent MI alone (odds ratio, 0.52 [95% CI, 0.30–0.81]). Conclusions: Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.

25-Hydroxy-Vitamin D and Risk of Recurrent Stroke: A Dose Response Meta-Analysis

“…Conversely, there is reasonable evidence that 25(OH)D levels equal or higher than 30 ng/mL reduce the risk of several, multifactorial, and complex diseases [ 59 ]. Nevertheless, our results are supported by genetic mendelian randomized studies [ 60 ].…”

“…The heterogeneity of the selected studies is caused by differences in the follow-up duration, the different cut-off of 25(OH)D levels and the different definitions of stroke type or outcome. Furthermore, the studies selected for this meta-analysis consider only 25(OH)D levels, without considering nutritional supplementation and solar ultra-violet B exposure, outperformed by genetic mendelian randomized studies [ 46 , 52 , 60 , 61 ]. In turn, the heterogeneity is tempered because three of the selected studies were conducted in the same country (China), and only one enrolled patients from the United Kingdom.…”

Genome-Wide Studies in Ischaemic Stroke: Are Genetics Only Useful for Finding Genes?

“…Perhaps the most interesting studies are those assessing causality using blood biomolecules as these are easy biomarkers to capture for stroke risk assessment but can also be potential drug targets. Not all the studies to date have observed causal associations with stroke risk, in either direction (inflammatory biomarkers [ 76 , 77 , 79 , 83 ], between circulating cytokines [ 96 ], vitamins [ 78 , 79 , 80 , 81 , 82 , 83 , 114 ], and many polyunsaturated fatty acids [ 70 ]). Some interesting findings are: (1) the identification of a causal link between lower serum MMP-12 levels and the risk of AIS, lower serum MMP-1 and MMP-12 levels and the risk of LAS, and higher serum MMP-8 levels and the risk of SVS [ 94 ]; (2) genetically determined levels of hemostatic factors have also been associated with the risk of IS [ 87 , 88 ]; (3) iron factors are causally associated with an increased risk of IS and CES, except transferrin, which is protective against IS and CES [ 73 ]; (4) among the cytokines studied, monocyte chemoattractant protein-1 (MCP-1) is the only one that was associated with an increased risk of IS, LAS, and CES [ 96 ].…”

Genetic Determinants of Vitamin D Deficiency in the Middle Eastern Qatari Population by a Genome-Wide Association Study

“…Until the present, multiple single-nucleotide polymorphisms (SNPs) have been identi ed at or near loci of genes encoding proteins responsible for Vitamin D transportation (GC, APOA1), biosynthesis (DHCR7, NADSYN1), metabolism (CYP2R1, RRAS2, PDE3B, CYP24A1, CYP27A1, CYP27B1, CYP11A1, SSTR4/FOXA2, AMDHD1, and SEC23A), and activity (VDR and RXRα, RXRβ, RXRγ) (8-12). Around 70 Mendelian randomization analyses have suggested a causal in uence estimation of Vitamin D through genetic variations (13)(14)(15)(16)(17)(18)(19). Detection of common genetic signatures (minor allele frequency (MAF) greater than 5%) that regulate Vitamin D status aids in providing detailed insight into physiological roles and mechanisms and in predicting individuals at risk of Vitamin D de ciency.…”