ANKS1A genotype predicts cardiovascular events in patients with familial hypercholesterolemia

Background The rs17609940 variant of the ANKS1A gene has been associated with coronary artery disease (CAD) risk in genome-wide association studies (GWAS), but no study has yet replicated this association in familial hypercholesterolemia (FH) population. Objective The aim of this study is to validate the association between the rs17609940 genotype and incident major adverse cardiovascular events (MACE) in a cohort of genetically-confirmed FH patients. Methods This association study includes 725 genetically-confirmed FH patients with a median observation period of 50 years (33 805 person-years). MACE were defined as either myocardial infarction (MI), stroke, coronary revascularization, hospital admission for unstable angina and cardiovascular disease (CVD) death. The rs17609940 genotype was imputed with an imputation quality of 0.831 following an exome chip genotyping method (Illumina). Results The cohort comprised 469 subjects with GG genotype, 218 subjects with CG genotype and 38 subjects with CC genotype. All baseline characteristics were balanced between the three groups. The CC genotype of rs17609940 was associated with a significant lower risk of incident MACE compared to GG and GC carriers in a recessive model (HR 0.30, 95% CI 0.11-0.82, p=0.02). Even after correction for confounding cardiovascular risk factors, the association between the ANKS1A polymorphism and incident MACE remained strongly significant. Conclusions We demonstrated that the rs17609940 SNP of the ANKS1A gene is associated with the risk of incident MACE in FH subjects. The exact mechanism underlying this association remains to be clarified.