@article{c1c5c755b205413792ae1dc6968aa6a0,
title = "LPA variants are associated with residual cardiovascular risk in patients receiving statins",
abstract = "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.",
keywords = "Cholesterol, Coronary disease, Electronic health records, Hydroxymethylglutaryl-CoA, LDL reductase inhibitors, Lysophosphatidic acid",
author = "Wei, {Wei Qi} and Xiaohui Li and Qiping Feng and Michiaki Kubo and Kullo, {Iftikhar J.} and Peissig, {Peggy L.} and Karlson, {Elizabeth W.} and Jarvik, {Gail P.} and Lee, {Ming Ta Michael} and Ning Shang and Larson, {Eric A.} and Todd Edwards and Shaffer, {Christian M.} and Mosley, {Jonathan D.} and Shiro Maeda and Momoko Horikoshi and Marylyn Ritchie and Williams, {Marc S.} and Larson, {Eric B.} and Crosslin, {David R.} and Bland, {Sarah T.} and Pacheco, {Jennifer A.} and Rasmussen-Torvik, {Laura J.} and David Cronkite and George Hripcsak and Cox, {Nancy J.} and Wilke, {Russell A.} and Stein, {C. Michael} and Rotter, {Jerome I.} and Yukihide Momozawa and Roden, {Dan M.} and Krauss, {Ronald M.} and Denny, {Joshua C.}",
note = "Funding Information: The project was supported by the eMERGE Network (phase III). This phase of the eMERGE Network was initiated and funded by the National Human Genome Research Institute through the following grants: U01HG8657 (Kaiser Perman-ente Washington/University of Washington); U01HG8685 (Brigham and Women{\textquoteright}s Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children{\textquoteright}s Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children{\textquoteright}s Hospital of Philadelphia); U01HG8673 (North-western University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine). The project was supported by National Institutes of Health grants R01 LM 010685, P50 GM115305, R01 HL133786, R01 GM103859, U01 HG008672, U19 HL69757, P50 GM115318, GM109145, GM120523, NIH National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881 and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center, and American Heart Association Scientist Development Grant 16SDG27490014. Funding Information: The project was supported by the eMERGE Network (phase III). This phase of the eMERGE Network was initiated and funded by the National Human Genome Research Institute through the following grants: U01HG8657 (Kaiser Permanente Washington/University of Washington); U01HG8685 (Brigham and Women's Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children's Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children's Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine). The project was supported by National Institutes of Health grants R01 LM 010685, P50 GM115305, R01 HL133786, R01 GM103859, U01 HG008672, U19 HL69757, P50 GM115318, GM109145, GM120523, NIH National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881 and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center, and American Heart Association Scientist Development Grant 16SDG27490014. Publisher Copyright: {\textcopyright} 2018 American Heart Association, Inc.",
year = "2018",
doi = "10.1161/CIRCULATIONAHA.117.031356",
language = "English (US)",
volume = "138",
pages = "1839--1849",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "17",
}