Long Wang1, Juan Chen1, Ying Zeng1, Jie Wei1, Jinjin Jing1, Ge Li1, Li Su1, Xiaojun Tang1, Tangchun Wu1, Li Zhou2. 1. 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.). 2. 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.
Abstract
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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: Kevin M Huang; Megan Zavorka Thomas; Tarek Magdy; Eric D Eisenmann; Muhammad Erfan Uddin; Duncan F DiGiacomo; Alexander Pan; Markus Keiser; Marcus Otter; Sherry H Xia; Yang Li; Yan Jin; Qiang Fu; Alice A Gibson; Ingrid M Bonilla; Cynthia A Carnes; Kara N Corps; Vincenzo Coppola; Sakima A Smith; Daniel Addison; Anne T Nies; Ralf Bundschuh; Taosheng Chen; Maryam B Lustberg; Joanne Wang; Stefan Oswald; Moray J Campbell; Pearlly S Yan; Sharyn D Baker; Shuiying Hu; Paul W Burridge; Alex Sparreboom Journal: Proc Natl Acad Sci U S A Date: 2021-02-02 Impact factor: 11.205
Authors: Jason T Anderson; Kevin M Huang; Maryam B Lustberg; Alex Sparreboom; Shuiying Hu Journal: Rev Physiol Biochem Pharmacol Date: 2022 Impact factor: 7.500