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Mendelian Randomization Focused Analysis of Vitamin D on the Secondary Prevention of Ischemic Stroke
Yap-Hang Chan1, C Mary Schooling2, Jie Zhao2
1Division of Cardiology, Queen Mary Hospital (Y.-H.C., J.J.H., Y.-K.W., K.-W.A., H.-F.T.), The University of Hong Kong, Hong Kong SAR, China.
Insights
Vitamin D (Vit-D) may prevent recurrent ischemic strokes and heart attacks in individuals with prior cardiovascular events. Genetically lower Vit-D levels are causally linked to an increased risk of these vascular events.
Area of Science:
- Cardiovascular Medicine
- Endocrinology
- Genetics
Background:
- Vitamin D (Vit-D) is known to promote vascular regeneration and repair.
- Previous studies primarily focused on Vit-D's role in primary prevention.
- The effect of Vit-D on secondary prevention of recurrent ischemic events was previously unknown.
Purpose of the Study:
- To investigate the potential protective effect of Vitamin D (Vit-D) against recurrent ischemic stroke and myocardial infarction (MI) in individuals with established ischemic disease.
- To utilize Mendelian randomization to establish a causal link between Vit-D levels and the secondary prevention of ischemic vascular events.
Main Methods:
- Developed a genetic risk score for Vit-D based on 12 genetic variants from a large derivation cohort (n=5331).
- Employed a 2-sample, individual-data, prospective Mendelian randomization approach.
- Analyzed a subsample (n=441) of patients with prior ischemic events for the recurrence of MI and ischemic stroke.
Main Results:
- A higher genetic risk score for Vit-D was associated with improved event-free survival from recurrent ischemic stroke or MI (P=0.001).
- The genetic risk score independently predicted a reduced risk of combined recurrent ischemic stroke or MI (HR, 0.62; P<0.001).
- Mendelian randomization indicated a causal protective effect of Vit-D against recurrent ischemic stroke/MI (OR, 0.55) and recurrent MI alone (OR, 0.52).
Conclusions:
- Genetically predicted lower Vitamin D (Vit-D) levels are causally associated with an increased risk of recurrent ischemic vascular events.
- Vit-D may play a crucial role in the secondary prevention of ischemic stroke and myocardial infarction.
- These findings support the potential therapeutic benefit of optimizing Vit-D levels in patients with prior ischemic insults.
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.
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