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

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.