BRG1 variant rs1122608 on chromosome 19p13.2 confers protection against stroke and regulates expression of pre-mRNA-splicing factor SFRS3

Xin Xiong, Chengqi Xu, Yuting Zhang, Xiuchun Li, Binbin Wang, Fan Wang, Qin Yang, Dan Wang, Xiaojing Wang, Sisi Li, Shanshan Chen, Yuanyuan Zhao, Dan Yin, Yufeng Huang, Xuan Zhu, Li Wang, Longfei Wang, Le Chang, Chaoping Xu, Hui LiTie Ke, Xiang Ren, Yanxia Wu, Rongfeng Zhang, Tangchun Wu, Yunlong Xia, Yanzong Yang, Xu Ma, Xin Tu, Qing K. Wang

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25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)499-508
Number of pages10
JournalHuman Genetics
Volume133
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgments this work was supported by grants from the national Basic research Program of China (973 Program: 2013CB531101 and 2012CB517800), the “Innovative Development of new Drugs” Key scientific Project (2011ZX09307-001-09), and nIH r01 Hl094498.

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