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Circulation. 2018 Oct 23;138(17):1839-1849. doi: 10.1161/CIRCULATIONAHA.117.031356.

LPA Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins.

Author information

1
Department of Biomedical Informatics (W.-Q.W., J.D.M., J.C.D.), Vanderbilt University Medical Center, Nashville, TN.
2
The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (X.L., J.I.R.).
3
Division of Clinical Pharmacology (Q.F., C.S., J.D.M., C.M.S., D.M.R.), Vanderbilt University Medical Center, Nashville, TN.
4
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (M.K., S.M., M.H., Y.M.).
5
Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (I.J.K.).
6
Center for Precision Medicine Research, Marshfield Clinic Research Institute, WI (P.L.P.).
7
Division of Rheumatology, Immunology and Allergy, Brigham & Women's Hospital and Harvard Medical School, Boston, MA (E.W.K.).
8
Departments of Medicine (Medical Genetics) and Genome Sciences (G.P.J., D.C.), University of Washington, Seattle.
9
Genomic Medicine Institute, Geisinger, Danville, PA (M.T.M.L., M.S.W.).
10
Department of Biomedical Informatics, Columbia University, New York, NY (N.S., G.H.).
11
Sanford School of Medicine, University of South Dakota, Sioux Falls (E.A.L., R.A.W.).
12
Vanderbilt Genetics Institute and the Division of Genetic Medicine, Vanderbilt University, Nashville, TN (T.E., N.J.C.).
13
Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan (S.M.).
14
Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan (S.M.).
15
Center for Translational Bioinformatics, Institute for Biomedical Informatics, Institute for Biomedical Informatics, Center for Precision Medicine, University of Pennsylvania, Philadelphia (M.R.).
16
Kaiser Permanente Washington Health Research Institute, Seattle (E.B.L., D.C.).
17
Department of Biomedical Informatics and Medical Education (D.R.C.), University of Washington, Seattle.
18
Vanderbilt Institute for Clinical and Translational Research (S.T.B.), Vanderbilt University Medical Center, Nashville, TN.
19
Feinberg School of Medicine, Northwestern University, Chicago, IL (J.A.P., L.J.R.-T.).
20
Department of Medicine (C.M.S., D.M.R., J.C.D.), Vanderbilt University Medical Center, Nashville, TN.
21
Children's Hospital Oakland Research Institute, CA (R.M.K.).

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:

LDL reductase inhibitors; cholesterol; coronary disease; electronic health records; hydroxymethylglutaryl-CoA; lysophosphatidic acid

PMID:
29703846
PMCID:
PMC6202211
[Available on 2019-10-23]
DOI:
10.1161/CIRCULATIONAHA.117.031356

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