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

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.

Association study of genetic variants at TTC32‐WDR35 gene cluster with coronary artery disease in Chinese Han population

“…The vessels were scored as follows: stenosis <50% in any major coronary artery was classified as 0‐vessel disease; a significant coronary lesion was defined as showing ≥50% stenosis in the luminal diameter in one or more coronary arteries. The major coronary artery disease, involving left main coronary artery disease, left anterior descending artery disease, right coronary artery disease, and left circumflex artery disease, was described in a previous study 17 …”

Elevated lipoprotein (a) levels are associated with the acute myocardial infarction in patients with normal low-density lipoprotein cholesterol levels

“…In our study, the diagnoses of AMI and non-CAD were verified by CAG examination and all of the participants did not take lipid-lowering drugs in the three months prior to the study, which might be lack of the effect of lipid-lowering drugs on the Lp(a) concentrations. Additionally, different LPA gene polymorphism across ethnicities leading to different Lp(a) concentrations might be another reason [22]. Furthermore, different methods of measurement also lead to the discrepancy of results [23].…”

The Interleukin 1 Receptor Type 1 Variant rs2234651 is a Risk Factor for Coronary Artery Disease in a Chinese Han Population: A Case Control Study

“…having ≥50% stenosis in the luminal diameter of one or more coronary arteries was defined as a significant coronary lesion. Major coronary artery disease included left main coronary artery disease (considered a two-vessel disease characterized by stenosis ≥50%), left anterior descending artery disease, left circumflex artery disease, and right coronary artery disease [28].…”