Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease

Akihiro Nomura, Hong Hee Won, Amit V. Khera, Fumihiko Takeuchi, Kaoru Ito, Shane McCarthy, Connor A. Emdin, Derek Klarin, Pradeep Natarajan, Seyedeh M. Zekavat, Namrata Gupta, Gina M. Peloso, Ingrid B. Borecki, Tanya M. Teslovich, Rosanna Asselta, Stefano Duga, Piera A. Merlini, Adolfo Correa, Thorsten Kessler, James G. WilsonMatthew J. Bown, Alistair S. Hall, Peter S. Braund, David J. Carey, Michael F. Murray, H. Lester Kirchner, Joseph B. Leader, Daniel R. Lavage, J. Neil Manus, Dustin N. Hartze, Nilesh J. Samani, Heribert Schunkert, Jaume Marrugat, Roberto Elosua, Ruth McPherson, Martin Farrall, Hugh Watkins, Jyh Ming J. Juang, Chao A. Hsiung, Shih Yi Lin, Jun Sing Wang, Hayato Tada, Masa Aki Kawashiri, Akihiro Inazu, Masakazu Yamagishi, Tomohiro Katsuya, Eitaro Nakashima, Masahiro Nakatochi, Ken Yamamoto, Mitsuhiro Yokota, DiscovEHR Study Group, TAICHI Consortium

Research output: Contribution to journalArticle

Abstract

Rationale: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. Objective: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). Conclusions: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.

Original languageEnglish
Pages (from-to)81-88
Number of pages8
JournalCirculation Research
Volume121
Issue number1
DOIs
Publication statusPublished - Jun 23 2017

Keywords

  • case-control studies
  • cholesteryl ester transfer protein
  • coronary disease
  • lipids

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Nomura, A., Won, H. H., Khera, A. V., Takeuchi, F., Ito, K., McCarthy, S., Emdin, C. A., Klarin, D., Natarajan, P., Zekavat, S. M., Gupta, N., Peloso, G. M., Borecki, I. B., Teslovich, T. M., Asselta, R., Duga, S., Merlini, P. A., Correa, A., Kessler, T., ... TAICHI Consortium (2017). Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease. Circulation Research, 121(1), 81-88. https://doi.org/10.1161/CIRCRESAHA.117.311145