SLC22A3 is associated with lipoprotein (a) concentration and cardiovascular disease in familial hypercholesterolemia

Background and aims: Several clinical and genetic factors have been shown to modulate the cardiovascular risk in subjects affected by familial hypercholesterolemia (FH). Genome wide association studies (GWAS) in the general population have identified several single nucleotide polymorphisms (SNPs) significantly associated with the risk of cardiovascular disease (CVD). This include the rs2048327 variant in the SLC22A3 gene. However, the effect of this SNP in FH subjects is unknown. The objectives of this study are to investigate the association between rs2048327 and the prevalence of CVD as well as with the concentration of lipoprotein (a) (Lp (a)), in a cohort of genetically-confirmed heterozygous FH patients. Methods: An enzyme-linked immunoassay kit was used to assess the Lp (a) concentration, whereas an exome chip genotyping method was used to impute the rs2048327 genotype. Results: The cohort comprised 287 non-carriers (TT), 305 heterozygous carriers (TC) and 76 homozygous carriers of the rs2048327 variant. In a model corrected for traditional cardiovascular risk factors, rs2048327 was significantly associated with Lp (a) level (median value of 12, 16 and 29 mg/dL in TT, TC and CC carriers, respectively, p < .0001). In a model corrected for cardiovascular risk factors and Lp(a) value, carrying the C allele was associated with a 2-fold increased risk of CVD (OR 1.96, 95%CI 1.21-3.19, p = .007). Conclusions: In this study, we demonstrated that the rs2048327 SNP of the SLC22A3 gene was significantly associated with Lp(a) as well as with CVD events in FH subjects. Further studies are required in order to investigate the mechanisms behind these associations.