LPA Variants are Associated with Residual Cardiovascular Risk in Patients Receiving Statins
Background—Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with HMG-CoA reductase inhibitors (statins) decreases circulating levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown.
Methods—We performed a two-stage genome-wide association study (GWAS) of CHD events during statin therapy. We first identified 3,099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7,681 controls without CHD events during comparable intensity and duration of statin therapy from four sites in the Electronic Medical Records and Genomics (eMERGE) Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth eMERGE site, which joined the network after the initial GWAS. Finally, we performed a phenome-wide association study (PheWAS) for other traits linked to the most significant locus.
Results—The meta-analysis identified seven SNPs at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic SNP within LPA/PLG (rs10455872, MAF=0.069, Odds Ratio [OR]=1.58, 95% CI [1.35-1.86], P=2.6×10−10). In the replication cohort, rs10455872 was also associated with CHD events (OR=1.71, 95% CI [1.14-2.57], p=0.009). The association of this SNP with CHD events was independent of statin-induced change in LDL-C (OR=1.62, 95% CI [1.17-2.24], p=0.004) and persisted in individuals with LDL-C≤70mg/dL (OR=2.43, 95% CI [1.18-4.75], p=0.015). PheWAS supported the effect of this region on coronary heart disease and did not identify non-cardiovascular phenotypes.
Conclusions—Genetic variations at the LPA locus is associated with CHD events during statin therapy independent of the extent of LDL-C lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.
- Received August 28, 2017.
- Revision received April 4, 2018.
- Accepted April 12, 2018.