Tai-Hing Lam1, Karen Siu-Ling Lam2, Hung-Fat Tse3,4,5,6, Yap-Hang Chan3, C Mary Schooling1, Jie Zhao1, Shiu-Lun Au Yeung1, Jo Jo Hai3,6, G Neil Thomas7, Kar-Keung Cheng7, Chao-Qiang Jiang8, Yuen-Kwun Wong3, Ka-Wing Au3, Clara S Tang9, Chloe Y Y Cheung2, Aimin Xu2, Pak-Chung Sham9. 1. 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. 2. 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. 3. 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. 4. Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (H.-F.T.), The University of Hong Kong, Hong Kong SAR, China. 5. Shenzhen Institutes of Research and Innovation (H.-F.T.), The University of Hong Kong, Hong Kong SAR, China. 6. Department of Medicine, Shenzhen Hong Kong University Hospital, China (J.J.H., H.-F.T.). 7. Department of Public Health and Epidemiology, University of Birmingham, United Kingdom (G.N.T., K.-K.C.). 8. Guangzhou No. 12 Hospital, People's Republic of China (C.-Q.J.). 9. Department of Psychiatry and Centre for Genomic Sciences (C.S.T., P.-C.S.), The University of Hong Kong, Hong Kong SAR, China.
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.
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.
Entities:
Keywords:
ischemic stroke; myocardial infarction; recurrence; secondary prevention; vitamin D
Authors: Tai-Hing Lam; Karen Siu-Ling Lam; Hung-Fat Tse; Yap-Hang Chan; C Mary Schooling; Jie V Zhao; Shiu-Lun Au Yeung; Jo Jo Hai; G Neil Thomas; Kar-Keung Cheng; Chao-Qiang Jiang; Yuen-Kwun Wong; Ka-Wing Au; Clara S Tang; Chloe Y Y Cheung; Aimin Xu; Pak-Chung Sham Journal: Genes Nutr Date: 2022-01-29 Impact factor: 5.523
Authors: Cristina Gallego-Fabrega; Elena Muiño; Jara Cárcel-Márquez; Laia Llucià-Carol; Miquel Lledós; Jesús M Martín-Campos; Natalia Cullell; Israel Fernández-Cadenas Journal: Int J Mol Sci Date: 2022-06-20 Impact factor: 6.208