title: NEXN is a novel susceptibility gene for coronary artery disease in Han Chinese.
abstract: Coronary artery disease (CAD) is the leading cause of death and disability in the world. Genome-wide association studies have implicated the importance of the genetic contribution of vascular smooth muscle cells (VSMCs) function in CAD susceptibility. The aberrant phenotypic modulation of VSMC is responsible for the pathological vascular intima hyperplasia that is the hallmark for atherosclerotic morphology. NEXN is a muscle-specific F-actin binding protein and is regulated by inflammatory cytokines in VSMCs. Whether NEXN contributes to human vascular disorders is still unknown. In this study, we genotyped 5 SNPs, tagging all of the 17 common SNPs within 54 kilobases (kb) covering NEXN gene and its flanking region, in 1883 patients with CAD and 1973 healthy individuals from Han Chinese, and identified one SNP, rs1780050, which was strongly associated with CAD trait. The Bonferroni corrected P-value was 7.65×10(-5). The odds ratio (95% confidence interval) was 1.23 (1.12-1.36) with statistical power of 0.994. Functional analysis showed that NEXN promotes VSMC to a contractile phenotype in vitro and inhibits balloon-injury induced neointima formation in vivo. Further eQTL analysis demonstrated that the risk allele T of rs1780050 is associated with decreased expression of NEXN, thus contributing to a higher risk of CAD susceptibility in the population. This is, to our knowledge, the first study to identify NEXN as a novel CAD susceptibility gene with both genetic and functional evidence.
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Cardiolody, Affiliated Hospital of Jining Medical University, Jining, China.
authors.forename: Jingzhi
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Gu-Yan
authors.initials: GY
authors.lastname: Zheng
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Tian
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Cao
mesh_terms: D000483:Alleles; D000800:Angioplasty, Balloon; D000818:Animals; D044466:Asian People; D002681:China; D003324:Coronary Artery Disease / Q000235:genetics* / Q000503:physiopathology; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D009200:Myocardial Contraction; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D008840:Microfilament Proteins; C501659:NEXN protein, human