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)]. However, the association between this gene cluster and the severity of coronary artery disease (CAD), especially the potential underlying mechanism, has not been clarified. The purpose of this study was to investigate the genetic role of the SLC22A3-LPAL2-LPA gene cluster in CAD. Approach and Results— We performed 2-stage case–control studies in a Chinese Han population. The variants were examined for the association with the Lp(a) level and severity of CAD. The molecular mechanism was explored. One single nucleotide polymorphism, rs3088442, in the SLC22A3-LPAL2-LPA gene cluster was significantly associated with CAD severity and plasma Lp(a) levels in a Chinese Han population. The gene dosage of rs3088442 indicated a robust association with left main trunk disease ( P =0.046), numbers 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 the altered regulation of SLC22A3 and LPA gene expression ( P =0.015 and 9.2×10–6, respectively) and finally increasing the plasma Lp(a) levels and risk of CAD. Conclusions— The genetic variant rs3088442 in the SLC22A3-LPAL2-LPA gene cluster seems to have a causal role in the regulation of the plasma Lp(a) level and contributes to the severity of CAD in a Chinese Han population.