LPA
Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins
Authors: Wei Wei-Qi , Li Xiaohui , Feng Qiping , Kubo Michiaki , Kullo Iftikhar J. , Peissig Peggy L. , Karlson Elizabeth W. , Jarvik Gail P. , Lee Ming Ta Michael , Shang Ning , Larson Eric A. , Edwards Todd , Shaffer Christian M. , Mosley Jonathan D. , Maeda Shiro , Horikoshi Momoko , Ritchie Marylyn , Williams Marc S. , Larson Eric B. , Crosslin David R. , Bland Harris T. , Pacheco Jennifer A. , Rasmussen-Torvik Laura J. , Cronkite David , Hripcsak George , Cox Nancy J. , Wilke Russell A. , Stein C. Michael , Rotter Jerome I. , Momozawa Yukihide , Roden Dan M. , Krauss Ronald M. , Denny Joshua C. 
Published: April 2018

Background:
Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol 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 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus.

Results:

The meta-analysis identified 7 single nucleotide polymorphisms 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 single nucleotide polymorphism within
LPA/PLG
(rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35–1.86;
P
=2.6×10
−
10
). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14–2.57;
P
=0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17–2.24;
P
=0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18–4.75;
P
=0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes.

Conclusions:

Genetic variations at the
LPA
locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.