title: BRG1 variant rs1122608 on chromosome 19p13.2 confers protection against stroke and regulates expression of pre-mRNA-splicing factor SFRS3.
abstract: A single nucleotide polymorphism (SNP) rs1122608 on chromosome 19p13.2 and in the BRG1/SMARCA4 gene was previously associated with coronary artery disease (CAD). CAD and ischemic stroke are both associated with atherosclerosis. Thus, we tested the hypothesis that rs1122608 is associated with ischemic stroke. Further studies were used to identify the most likely mechanism by which rs1122608 regulates atherosclerosis. For case-control association studies, two independent Chinese Han GeneID cohorts were used, including a Central cohort with 1,075 cases and 2,685 controls and the Northern cohort with 1,208 cases and 824 controls. eQTL and real-time RT-PCR analyses were used to identify the potential candidate gene(s) affected by rs1122608. The minor allele T of SNP rs1122608 showed significant association with a decreased risk of ischemic stroke in the Central GeneID cohort (adjusted P adj = 2.1 × 10(-4), OR 0.61). The association was replicated in an independent Northern GeneID cohort (P adj = 6.00 × 10(-3), OR 0.69). The association became more significant in the combined population (P adj = 7.86 × 10(-5), OR 0.73). Allele T of SNP rs1122608 also showed significant association with a decreased total cholesterol level (P adj = 0.013). Allele T of rs1122608 was associated with an increased expression level of SFRS3 encoding an mRNA splicing regulator, but not with the expression of BRG1/SMARCA4 or LDLR (located 36 kb from rs1122608). Increased expression of SFSR3 may decrease IL-1β expression and secretion, resulting in reduced risk of atherosclerosis and stroke. This is the first study that demonstrates that rs1122608 confers protection against ischemic stroke and implicates splicing factor SFSR3 in the disease process.
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xin
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authors.lastname: Xiong
authors.forename: Chengqi
authors.initials: C
authors.lastname: Xu
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiuchun
authors.initials: X
authors.lastname: Li
authors.forename: Binbin
authors.initials: B
authors.lastname: Wang
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.forename: Sisi
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authors.lastname: Li
authors.forename: Shanshan
authors.initials: S
authors.lastname: Chen
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Dan
authors.initials: D
authors.lastname: Yin
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Huang
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhu
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Longfei
authors.initials: L
authors.lastname: Wang
authors.forename: Le
authors.initials: L
authors.lastname: Chang
authors.forename: Chaoping
authors.initials: C
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Tie
authors.initials: T
authors.lastname: Ke
authors.forename: Xiang
authors.initials: X
authors.lastname: Ren
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Wu
authors.forename: Rongfeng
authors.initials: R
authors.lastname: Zhang
authors.forename: Tangchun
authors.initials: T
authors.lastname: Wu
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Xia
authors.forename: Yanzong
authors.initials: Y
authors.lastname: Yang
authors.forename: Xu
authors.initials: X
authors.lastname: Ma
authors.forename: Xin
authors.initials: X
authors.lastname: Tu
authors.forename: Qing K
authors.initials: QK
authors.lastname: Wang
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002888:Chromosomes, Human, Pair 19; D004265:DNA Helicases / Q000235:genetics*; D017931:DNA Primers; D006801:Humans; D008055:Lipids / Q000097:blood; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D040641:Quantitative Trait Loci; D016601:RNA-Binding Proteins / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors; D020521:Stroke / Q000235:genetics* / Q000517:prevention & control; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D017931:DNA Primers; D008055:Lipids; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C491388:SRSF3 protein, human; D014157:Transcription Factors; D000068103:Serine-Arginine Splicing Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases