Abstract
Introduction: Lipoprotein (a) [Lp(a)] consists of a low-density lipoprotein (LDL) molecule attached to apolipoprotein(a) [apo(a)]. Apo(a) comprises two kringle domains (KIV and KV) derived from the plasminogen gene and an inactive protease domain. The KIV domain is subdivided into 10 subtypes (KIV1-10), with KIV2 occurring as a copy number variation (CNV) that varies among individuals. Elevated Lp(a) levels are a major risk factor for CVDs and are inversely correlated to the KIV2 CNV determining apo(a) isoform size. Objectives: This study aimed to identify variants associated with a high Lp(a) phenotype that were not linked to apo(a) isoform size.
Methods: Illumina sequencing of 13 candidate genes was performed on a discovery set comprising 54 high Lp(a) European samples (>50mg/dL). The sequenced genes included LPA, adjacent genes, and those coding for receptors involved in Lp(a) uptake. Variants commonly found in high samples were genotyped in the Otago LPA European cohort (n=589) and their association with Lp(a) levels was checked via Kruskal-Wallis and linear regression statistical models. The associations were then replicated in the much bigger German Chronic Kidney Disease (GCKD) cohort (n=4930).
Results: Nine variants were significantly associated with high Lp(a) levels. Two variants were in the LPA gene (rs3124784 and rs3798220) and seven were in neighbouring genes (rs2282143 in SLC22A1, rs3127592, rs3127593, rs3103353 and rs3127594 in SLC22A2 and rs1810126 and rs3088442 in SLC22A3). Interestingly, the minor allele of all nine variants was significantly associated with increased LPA expression in liver tissues in the GTEx database. Seven of the variants were significantly associated with small apo(a) isoform size (P=1x10-4 to 2.9x10-18), while rs1810126 and rs3088442 in SLC22A3 were not associated with the small isoform size (P=0.43 and 0.42).
Conclusion: Nine variants in the LPA and nearby genes were significantly associated with elevated Lp(a) levels and increased LPA expression, with the majority being linked to a short apo(a) isoform. The association of two SLC22A3 gene variants with Lp(a) levels independent of apo(a) isoform size warrants further investigation to establish any functional connection between LPA and this gene.