Mendelian randomization analysis of vitamin D in the secondary prevention of hypertensive-diabetic subjects: role of facilitating blood pressure control

• Published in: Genes & nutrition Vol. 17; no. 1; p. 1
• Main Authors: Chan, Yap-Hang, Schooling, C. Mary, Zhao, Jie V., Yeung, Shiu-Lun Au, 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: Germany BioMed Central 29.01.2022
• Subjects: 25-Hydroxyvitamin D; Angina; Blood pressure; blood serum; Cardiovascular diseases; Cerebral infarction; Cholesterol; Congestive heart failure; Creatinine; death; Diabetes; Diabetes mellitus (non-insulin dependent); Enzymes; Genomes; Glucose; Health risk assessment; heart failure; High density lipoprotein; Hypertension; Hypotheses; Ischemia; Myocardial infarction; noninsulin-dependent diabetes mellitus; risk; Single-nucleotide polymorphism; stroke; Triglycerides; Vascular diseases; Vitamin D; United States > US; Hypertension; Type 2 diabetes; Vitamin D; Secondary prevention; Chinese; Mendelian randomization; Exome Chip
• ISSN: 1555-8932; 1865-3499
• DOI: 10.1186/s12263-022-00704-z

Vitamin D (Vit-D) promotes vascular repair and its deficiency is closely linked to the development of type 2 diabetes mellitus (T2DM) and hypertension. Whether genetially predicted vitamin D status (serological 25-hydroxyvitamin D [25(OH)D]) confers secondary protection against cardiovascular diseases (CVD) among high-risk hypertensive-diabetic subjects was unknown. This is a prospective, individual-data, two-sample Mendelian randomization study. We interrogated 12 prior GWAS-detected SNPs of comprehensive Vit-D mechanistic pathways using high-throughput exome chip analyses in a derivation subcohort (n = 1460) and constructed a genetic risk score (GRS) (rs2060793, rs4588, rs7041; F-statistic = 32, P < 0.001) for causal inference of comprehensive CVD hard clinical endpoints in an independent sample of hypertensive subjects (n = 3746) with prevailing co-morbid T2DM (79%) and serological 25(OH)D deficiency [< 20 ng/mL] 45%. After 55.6 ± 28.9 months, 561 (15%) combined CVD events including myocardial infarction, unstable angina, ischemic stroke, congestive heart failure, peripheral vascular disease, and cardiovascular death had occurred. Kaplan-Meier analysis showed that genetically predicted reduced vitamin D status was associated with reduced event-free survival from combined CVD events (log-rank = 13.5, P = 0.001). Multivariate-adjusted per-allele increase in GRS predicted reduced combined CVD events (HR = 0.90 [0.84 to 0.96], P = 0.002). Mendelian randomization indicates that increased Vit-D exposure, leveraged through each 1 ng/mL genetically instrumented rise of serum Vit-D, protects against combined CVD events (Wald's estimate: OR = 0.86 [95%CI 0.75 to 0.95]), and myocardial infarction (OR = 0.76 [95%CI 0.60 to 0.90]). Furthermore, genetically predicted increase in Vit-D status ameliorates risk of deviation from achieving guideline-directed hypertension control (JNC-8: systolic target < 150 mmHg) (OR = 0.89 [95%CI 0.80 to 0.96]). Genetically predicted increase in Vit-D status [25(OH)D] may confer secondary protection against incident combined CVD events and myocardial infarction in a hypertensive-diabetic population where serological 25(OH)D deficiency is common, through facilitating blood pressure control.