title: Functional Variant in the SLC22A3-LPAL2-LPA Gene Cluster Contributes to the Severity of Coronary Artery Disease.
abstract: Recent genome-wide association studies have identified that genetic variants in the SLC22A3-LPAL2-LPA gene cluster influence plasma lipoprotein(a) [Lp(a)] concentration. However, the association between this gene cluster and the severity of coronary artery disease (CAD), especially the potential underlying mechanism, remains unclear. The purpose of this study was to investigate the association between variation in the SLC22A3-LPAL2-LPA gene cluster and CAD.
  
  
  
  We performed 2-stage case-control studies in a Chinese Han population. The variant genotypes were examined for their association with both Lp(a) level and severity of CAD. Putative mechanisms were also evaluated. One single nucleotide polymorphism, rs3088442, in the SLC22A3-LPAL2-LPA gene cluster was significantly associated with both plasma Lp(a) levels and CAD severity. The gene dosage of the risk allele at rs3088442 indicated a robust association with left main trunk disease (P=0.046), number of vascular lesions (P=4.5×10(-3)), and Gensini scores (P=0.012) in patients with CAD. Reporter gene analysis indicated that the rs3088442 G allele might suppress miR-147a binding to the 3' untranslated region of SLC22A3, resulting in altered SLC22A3 and LPA gene expression (P=0.015 and 9.2×10(-6), respectively), possibly explaining the increased plasma Lp(a) levels and risk of CAD.
  
  
  
  The genotype of rs3088442 within the SLC22A3-LPAL2-LPA gene cluster may contribute to regulation of plasma Lp(a) levels and possibly to the severity of CAD in a Chinese Han population.
authors.affiliation: From the Department of Epidemiology, Research Center for Medicine and Social Development, School of Public Health and Management (L.W., J.W., G.L., X.T., L.Z.); the Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital (J.C.) and the Department of Cardiology, the Second Affiliated Hospital and the Chongqing Cardiac Arrhythmias Service Center (J.J., L.S.), Chongqing Medical University, Chongqing, China; the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.Z.); and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China (T.W.).
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: From the Department of Epidemiology, Research Center for Medicine and Social Development, School of Public Health and Management (L.W., J.W., G.L., X.T., L.Z.); the Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital (J.C.) and the Department of Cardiology, the Second Affiliated Hospital and the Chongqing Cardiac Arrhythmias Service Center (J.J., L.S.), Chongqing Medical University, Chongqing, China; the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.Z.); and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China (T.W.).
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Department of Epidemiology, Research Center for Medicine and Social Development, School of Public Health and Management (L.W., J.W., G.L., X.T., L.Z.); the Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital (J.C.) and the Department of Cardiology, the Second Affiliated Hospital and the Chongqing Cardiac Arrhythmias Service Center (J.J., L.S.), Chongqing Medical University, Chongqing, China; the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.Z.); and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China (T.W.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: From the Department of Epidemiology, Research Center for Medicine and Social Development, School of Public Health and Management (L.W., J.W., G.L., X.T., L.Z.); the Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital (J.C.) and the Department of Cardiology, the Second Affiliated Hospital and the Chongqing Cardiac Arrhythmias Service Center (J.J., L.S.), Chongqing Medical University, Chongqing, China; the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.Z.); and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China (T.W.).
authors.forename: Jie
authors.initials: J
authors.lastname: Wei
authors.affiliation: From the Department of Epidemiology, Research Center for Medicine and Social Development, School of Public Health and Management (L.W., J.W., G.L., X.T., L.Z.); the Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital (J.C.) and the Department of Cardiology, the Second Affiliated Hospital and the Chongqing Cardiac Arrhythmias Service Center (J.J., L.S.), Chongqing Medical University, Chongqing, China; the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.Z.); and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China (T.W.).
authors.forename: Jinjin
authors.initials: J
authors.lastname: Jing
authors.affiliation: From the Department of Epidemiology, Research Center for Medicine and Social Development, School of Public Health and Management (L.W., J.W., G.L., X.T., L.Z.); the Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital (J.C.) and the Department of Cardiology, the Second Affiliated Hospital and the Chongqing Cardiac Arrhythmias Service Center (J.J., L.S.), Chongqing Medical University, Chongqing, China; the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.Z.); and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China (T.W.).
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.affiliation: From the Department of Epidemiology, Research Center for Medicine and Social Development, School of Public Health and Management (L.W., J.W., G.L., X.T., L.Z.); the Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital (J.C.) and the Department of Cardiology, the Second Affiliated Hospital and the Chongqing Cardiac Arrhythmias Service Center (J.J., L.S.), Chongqing Medical University, Chongqing, China; the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.Z.); and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China (T.W.).
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.affiliation: From the Department of Epidemiology, Research Center for Medicine and Social Development, School of Public Health and Management (L.W., J.W., G.L., X.T., L.Z.); the Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital (J.C.) and the Department of Cardiology, the Second Affiliated Hospital and the Chongqing Cardiac Arrhythmias Service Center (J.J., L.S.), Chongqing Medical University, Chongqing, China; the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.Z.); and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China (T.W.).
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Tang
authors.affiliation: From the Department of Epidemiology, Research Center for Medicine and Social Development, School of Public Health and Management (L.W., J.W., G.L., X.T., L.Z.); the Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital (J.C.) and the Department of Cardiology, the Second Affiliated Hospital and the Chongqing Cardiac Arrhythmias Service Center (J.J., L.S.), Chongqing Medical University, Chongqing, China; the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.Z.); and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China (T.W.).
authors.forename: Tangchun
authors.initials: T
authors.lastname: Wu
authors.affiliation: From the Department of Epidemiology, Research Center for Medicine and Social Development, School of Public Health and Management (L.W., J.W., G.L., X.T., L.Z.); the Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital (J.C.) and the Department of Cardiology, the Second Affiliated Hospital and the Chongqing Cardiac Arrhythmias Service Center (J.J., L.S.), Chongqing Medical University, Chongqing, China; the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China (Y.Z.); and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China (T.W.). zhouli_tj@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D016633:Apolipoprotein A-II / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D001665:Binding Sites; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood / Q000000981:diagnostic imaging / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D056426:Genetic Loci; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012720:Severity of Illness Index; D000099254:Organic Cation Transporter 3
chemical_list: D020413:3' Untranslated Regions; D016633:Apolipoprotein A-II; D005819:Genetic Markers; D017270:Lipoprotein(a); D035683:MicroRNAs; D027701:Organic Cation Transport Proteins; D000099254:Organic Cation Transporter 3; C115794:APOA2 protein, human; C572377:MIRN147 microRNA, human
keywords: SLC22A3-LPAL2-LPA; coronary artery disease; genome-wide association study; severity; single nucleotide polymorphism