The 9p21.3 locus and cardiovascular risk in familial hypercholesterolemia

Background: Carrying a risk variant in the 9p21.3 locus represents one of the strongest genetic risk factors for atherosclerotic cardiovascular disease (ASCVD) in the general population. However, the effect of these polymorphisms in patients with familial hypercholesterolemia (FH) has never been studied.

Objective: The objective of this study was to investigate the association between the sentinel 9p21.3 single nucleotide polymorphisms (SNP) rs1333047 and ASCVD susceptibility in FH subjects.

Methods: A total of 20,434 Caucasian patients with dyslipidemia were screened, of which 725 FH were included in this study. The risk allele (T) of the rs1333047 SNP has previously been shown to confer increased ASCVD risk compared with the control allele (A).

Results: In a model adjusted for traditional cardiovascular risk factors, carrying the risk allele was associated with a 42% increased ASCVD susceptibility per allele, according to an additive model (odds ratio = 1.42; 95% confidence interval, 1.05-1.91; P = .02). On average, 0.53 cardiovascular event was observed in AA carriers, compared with 0.83 in the TT group (P = .02). The mean age of first ASCVD event was similar among the 3 variants.

Conclusion: The 9p21.3 SNP rs1333047 SNP was associated with increased ASCVD in FH subjects. Genetic screening for this SNP could allow to identify very high risk FH patients, which could benefit from more aggressive ASCVD prevention.