LPA variants are associated with residual cardiovascular risk in patients receiving statins

Wei Qi Wei, Xiaohui Li, Qiping Feng, Michiaki Kubo, Iftikhar J. Kullo, Peggy L. Peissig, Elizabeth W. Karlson, Gail P. Jarvik, Ming Ta Michael Lee, Ning Shang, Eric A. Larson, Todd Edwards, Christian M. Shaffer, Jonathan D. Mosley, Shiro Maeda, Momoko Horikoshi, Marylyn Ritchie, Marc S. Williams, Eric B. Larson, David R. CrosslinSarah T. Bland, Jennifer A. Pacheco, Laura J. Rasmussen-Torvik, David Cronkite, George Hripcsak, Nancy J. Cox, Russell A. Wilke, C. Michael Stein, Jerome I. Rotter, Yukihide Momozawa, Dan M. Roden, Ronald M. Krauss, Joshua C. Denny

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1839-1849
Number of pages11
JournalCirculation
Volume138
Issue number17
DOIs
Publication statusPublished - 01-01-2018

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Coronary Disease
LDL Cholesterol
Odds Ratio
Confidence Intervals
Single Nucleotide Polymorphism
Electronic Health Records
Genome-Wide Association Study
Genomics
Therapeutics
Lipoprotein(a)
Gene Frequency
Meta-Analysis
Cause of Death
Myocardial Infarction

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Wei, W. Q., Li, X., Feng, Q., Kubo, M., Kullo, I. J., Peissig, P. L., ... Denny, J. C. (2018). LPA variants are associated with residual cardiovascular risk in patients receiving statins. Circulation, 138(17), 1839-1849. https://doi.org/10.1161/CIRCULATIONAHA.117.031356
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, Sarah 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. / LPA variants are associated with residual cardiovascular risk in patients receiving statins. In: Circulation. 2018 ; Vol. 138, No. 17. pp. 1839-1849.
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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.",
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.}",
year = "2018",
month = "1",
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doi = "10.1161/CIRCULATIONAHA.117.031356",
language = "English",
volume = "138",
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Wei, WQ, Li, X, Feng, Q, Kubo, M, Kullo, IJ, Peissig, PL, Karlson, EW, Jarvik, GP, Lee, MTM, Shang, N, Larson, EA, Edwards, T, Shaffer, CM, Mosley, JD, Maeda, S, Horikoshi, M, Ritchie, M, Williams, MS, Larson, EB, Crosslin, DR, Bland, ST, Pacheco, JA, Rasmussen-Torvik, LJ, Cronkite, D, Hripcsak, G, Cox, NJ, Wilke, RA, Stein, CM, Rotter, JI, Momozawa, Y, Roden, DM, Krauss, RM & Denny, JC 2018, 'LPA variants are associated with residual cardiovascular risk in patients receiving statins', Circulation, vol. 138, no. 17, pp. 1839-1849. https://doi.org/10.1161/CIRCULATIONAHA.117.031356

LPA variants are associated with residual cardiovascular risk in patients receiving statins. / 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, Sarah 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.

In: Circulation, Vol. 138, No. 17, 01.01.2018, p. 1839-1849.

Research output: Contribution to journalArticle

TY - JOUR

T1 - LPA variants are associated with residual cardiovascular risk in patients receiving statins

AU - Wei, Wei Qi

AU - Li, Xiaohui

AU - Feng, Qiping

AU - Kubo, Michiaki

AU - Kullo, Iftikhar J.

AU - Peissig, Peggy L.

AU - Karlson, Elizabeth W.

AU - Jarvik, Gail P.

AU - Lee, Ming Ta Michael

AU - Shang, Ning

AU - Larson, Eric A.

AU - Edwards, Todd

AU - Shaffer, Christian M.

AU - Mosley, Jonathan D.

AU - Maeda, Shiro

AU - Horikoshi, Momoko

AU - Ritchie, Marylyn

AU - Williams, Marc S.

AU - Larson, Eric B.

AU - Crosslin, David R.

AU - Bland, Sarah T.

AU - Pacheco, Jennifer A.

AU - Rasmussen-Torvik, Laura J.

AU - Cronkite, David

AU - Hripcsak, George

AU - Cox, Nancy J.

AU - Wilke, Russell A.

AU - Stein, C. Michael

AU - Rotter, Jerome I.

AU - Momozawa, Yukihide

AU - Roden, Dan M.

AU - Krauss, Ronald M.

AU - Denny, Joshua C.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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DO - 10.1161/CIRCULATIONAHA.117.031356

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