LDL-c-linked SNPs are associated with LDL-c and myocardial infarction despite lipid-lowering therapy in patients with established vascular disease

Abstract

Background: Several single-nucleotide polymorphisms (SNPs) are associated with both plasma low-density lipoprotein cholesterol (LDL-c) level and coronary artery disease in the general population. It is unclear whether these associations also apply to patients with vascular disease and whether the associations are independent of lipid-lowering therapy. Design: Single-nucleotide polymorphisms associated with plasma LDL-c and vascular risk in the general population (rs11206510 (PCSK9), rs1122608 (LDLR), rs579459 (ABO) and rs599839 (SORT1)) were genotyped in a prospective cohort study of 5482 patients with vascular disease. We determined the association between LDL-c-associated alleles and plasma LDL-c levels and the risk of new vascular events. Results: All tested SNPs were associated with LDL-c plasma levels with a magnitude between +0·06 (95% CI 0·02-0·10) mM and +0·14 (95% CI 0·09-0·18) mM per LDL-c-increasing allele. The associations were independent of the use of lipid-lowering medication, except for rs579459, for which the association was not present in patients using lipid-lowering medication. In patients with 7-8 risk alleles for these SNPs, 59% of the patients treated with lipid-lowering medication did not reach the LDL-c target of <2·5 mM compared with 45% in patients with 3 or fewer risk alleles. LDL-c-increasing alleles were not associated with increased risk of vascular events in patients not using lipid-lowering medication (HRs: 1·01; 95% CI: 0·93-1·09). In patients using lipid-lowering medication, the risk of myocardial infarction increased with 14% (HRs: 1·14; 95% CI: 1·01-1·28) per allele. Conclusions: In patients with established vascular disease, the studied SNPs increase LDL-c plasma levels. LDL-c-increasing alleles may be associated with increased risk of myocardial infarction in patients treated with lipid-lowering medication, but not in patients not treated with lipid-lowering medication. © 2013 Stichting European Society for Clinical Investigation Journal Foundation.