SLC22A3-LPAL2-LPA基因簇中的功能性变异与冠状动脉疾病的严重程度相关。

Functional Variant in the SLC22A3-LPAL2-LPA Gene Cluster Contributes to the Severity of Coronary Artery Disease.

作者信息

Wang Long, Chen Juan, Zeng Ying, Wei Jie, Jing Jinjin, Li Ge, Su Li, Tang Xiaojun, Wu Tangchun, Zhou Li

机构信息

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.).

出版信息

Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1989-96. doi: 10.1161/ATVBAHA.116.307311. Epub 2016 Jul 14.

DOI:10.1161/ATVBAHA.116.307311

PMID:27417586

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.

摘要

目的

近期全基因组关联研究已确定，溶质载体家族22成员3（SLC22A3）-脂蛋白A2样蛋白（LPAL2）-载脂蛋白A（LPA）基因簇中的遗传变异会影响血浆脂蛋白(a) [Lp(a)]浓度。然而，该基因簇与冠状动脉疾病（CAD）严重程度之间的关联，尤其是潜在的潜在机制，仍不清楚。本研究的目的是调查SLC22A3-LPAL2-LPA基因簇变异与CAD之间的关联。

方法与结果

我们在中国汉族人群中进行了两阶段病例对照研究。检查变异基因型与Lp(a)水平和CAD严重程度的关联。还评估了潜在机制。SLC22A3-LPAL2-LPA基因簇中的一个单核苷酸多态性rs3088442与血浆Lp(a)水平和CAD严重程度均显著相关。rs3088442风险等位基因的基因剂量与CAD患者的左主干疾病（P=0.046）、血管病变数量（P=4.5×10-3）和Gensini评分（P=0.012）呈强关联。报告基因分析表明，rs3088442 G等位基因可能抑制miR-147a与SLC22A3 3'非翻译区的结合，导致SLC22A3和LPA基因表达改变（分别为P=0.015和9.2×10-6），这可能解释了血浆Lp(a)水平升高和CAD风险增加的原因。