Identification of six polymorphisms as novel susceptibility loci for ischemic or hemorrhagic stroke by exome-wide association studies

Abstract

In this study, we performed exome-wide association studies (EWASs) to identify genetic variants that confer susceptibility to ischemic stroke, intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). EWAS for ischemic stroke was performed using 1,575 patients with this condition and 9,210 controls, and EWASs for ICH and SAH were performed using 673 patients with ICH, 265 patients with SAH and 9,158 controls. Analyses were performed with Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of allele frequencies for 41,339 or 41,332 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic or hemorrhagic stroke, respectively, was examined with Fisher's exact test. Based on Bonferroni's correction, a P-value of <1.21×10−6 was considered statistically significant. EWAS for ischemic stroke revealed that 77 SNPs were significantly associated with this condition. Multivariable logistic regression analysis with adjustment for age, sex and the prevalence of hypertension and diabetes mellitus revealed that 4 of these SNPs [rs3212335 of GABRB3 (P=0.0036; odds ratio, 1.29), rs147783135 of TMPRSS7 (P=0.0024; odds ratio, 0.37), rs2292661 of PDIA5 (P=0.0054; odds ratio, 0.35) and rs191885206 of CYP4F12 (P=0.0082; odds ratio, 2.60)] were related (P<0.01) to ischemic stroke. EWASs for ICH or SAH revealed that 48 and 12 SNPs, respectively, were significantly associated with these conditions. Multivariable logistic regression analysis with adjustment for age, sex and the prevalence of hypertension revealed that rs138533962 of STYK1 (P<1.0×10−23; odds ratio, 111.3) was significantly (P<2.60×10−4) associated with ICH and that rs117564807 of COL17A1 (P=0.0009; odds ratio, 2.23×10−8) was significantly (P<0.0010) associated with SAH. GABRB3, TMPRSS7, PDIA5 and CYP4F12 may thus be novel susceptibility loci for ischemic stroke, whereas STYK1 and COL17A1 may be such loci for ICH and SAH, respectively.

Identification of nine genes as novel susceptibility loci for early‑onset ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage

“…In our previous study ( 47 ), the median age of subjects with ischemic stroke, ICH, or SAH was 74, 71, or 60 years, respectively. We thus defined patients aged ≤65 years as early-onset cases in the present study.…”

“…We previously showed that four, six, or three SNPs were associated with ischemic stroke (P<0.01), ICH (P<0.05), or SAH (P<0.05), respectively, as determined by multivariable logistic regression analysis with adjustment for covariates after the initial EWAS screening among both early- and late-onset subjects with these conditions ( 47 ). The relationship of four SNPs to ischemic stroke was not replicated (P<0.05) in the present study.…”

Genetic susceptibility to cerebrovascular disease: A systematic review

“…27 One of these variants (rs4520) involves a silent T-C substitution and was suggested to confer increased risk for ischemic stroke in the Chinese Han population; the other, a 3 0 UTR (rs5128) polymorphism, was actually identified as a protective factor for ischemic stroke in this population. 27 In an exome-wide association study of a Japanese cohort, Yamada et al 28 identified three different coding variants associated with ischemic stroke: two protecting alleles involving TMPRSS7 and PDIA5 and a predisposing allele in CYP4F12. TMPRSS7 encodes a serine protease involved in degradation of the extracellular membrane.…”

“…28 The 391T > M polymorphism (rs2292661) was labeled an additional protective factor. 28 CYP4F12 encodes a P450 enzyme thought to be an endoplasmic reticulum protein involved in the metabolism of inflammatory mediators. 28 The 402C > R polymorphism (rs191885206) was correlated with increased risk of ischemic stroke.…”

“…28 CYP4F12 encodes a P450 enzyme thought to be an endoplasmic reticulum protein involved in the metabolism of inflammatory mediators. 28 The 402C > R polymorphism (rs191885206) was correlated with increased risk of ischemic stroke. 28 In a meta-analysis of over 2000 American and Chinese individuals, Ma et al 29 indicated the 82G > S variant (rs2070600) of RAGE as a risk marker for ischemic stroke.…”