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

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....

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Published inStroke (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
LanguageEnglish
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
Online AccessGet full text
ISSN0039-2499
1524-4628
1524-4628
DOI10.1161/STROKEAHA.120.032634

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Abstract 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.
AbstractList 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.
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.BACKGROUND AND PURPOSEExperimental 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 (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.METHODSBased 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.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]).RESULTSIn 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]).Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.CONCLUSIONSGenetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.
Author Thomas, G. Neil
Cheng, Kar-Keung
Jiang, Chao-Qiang
Cheung, Chloe Y.Y.
Wong, Yuen-Kwun
Tang, Clara S.
Chan, Yap-Hang
Au Yeung, Shiu-Lun
Hai, Jo Jo
Xu, Aimin
Tse, Hung-Fat
Schooling, C. Mary
Sham, Pak-Chung
Lam, Tai-Hing
Zhao, Jie
Au, Ka-Wing
Lam, Karen Siu-Ling
AuthorAffiliation School of Public Health (C.M.S., J.Z., S.-L.A.Y., T.-H.L.), The University of Hong Kong, Hong Kong SAR, China
Department of Public Health and Epidemiology, University of Birmingham, United Kingdom (G.N.T., K.-K.C.)
Guangzhou No. 12 Hospital, People’s Republic of China (C.-Q.J.)
Division 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
Division of Endocrinology, Queen Mary Hospital (C.Y.Y.C., A.X., K.S.-L.L.), The University of Hong Kong, Hong Kong SAR, China
Department of Psychiatry and Centre for Genomic Sciences (C.S.T., P.-C.S.), The University of Hong Kong, Hong Kong SAR, China
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/34565175$$D View this record in MEDLINE/PubMed
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Keywords recurrence
secondary prevention
vitamin D
ischemic stroke
myocardial infarction
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Snippet Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary...
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SubjectTerms 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
Title Mendelian Randomization Focused Analysis of Vitamin D on the Secondary Prevention of Ischemic Stroke
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