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

• Published in: Stroke (1970) Vol. 52; no. 12; pp. 3926 - 3937
• Main Authors: Chan, Yap-Hang, Schooling, C. Mary, Zhao, Jie, Au Yeung, Shiu-Lun, Hai, Jo Jo, Thomas, G. Neil, Cheng, Kar-Keung, Jiang, Chao-Qiang, Wong, Yuen-Kwun, Au, Ka-Wing, Tang, Clara S., Cheung, Chloe Y.Y., Xu, Aimin, Sham, Pak-Chung, Lam, Tai-Hing, Lam, Karen Siu-Ling, Tse, Hung-Fat
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 01.12.2021
• Subjects: Adult; Aged; Female; Genome-Wide Association Study; Genotype; Humans; Ischemic Stroke - blood; Ischemic Stroke - genetics; Male; Mendelian Randomization Analysis; Middle Aged; Myocardial Infarction - blood; Myocardial Infarction - genetics; Polymorphism, Single Nucleotide; Secondary Prevention - methods; Vitamin D - blood; Vitamin D - genetics; recurrence; secondary prevention; vitamin D; ischemic stroke; myocardial infarction
• ISSN: 0039-2499; 1524-4628; 1524-4628
• DOI: 10.1161/STROKEAHA.120.032634

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. 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 ( , , and ; F statistic, 73; <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. 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; =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]; <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]). Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.