Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance
Author(s)Nomura, Akihiro; Won, Hong-Hee; Khera, Amit V.; Takeuchi, Fumihiko; Ito, Kaoru; McCarthy, Shane; Emdin, Connor A.; Klarin, Derek; Natarajan, Pradeep; Gupta, Namrata; Peloso, Gina M.; Borecki, Ingrid B.; Teslovich, Tanya M.; Asselta, Rosanna; Duga, Stefano; Merlini, Piera A.; Correa, Adolfo; Kessler, Thorsten; Wilson, James G.; Bown, Matthew J.; Hall, Alistair S.; Braund, Peter S.; Carey, David J.; Kirchner, H. Lester; Leader, Joseph B.; Lavage, Daniel R.; Manus, J. Neil; Hartze, Dustin N.; Samani, Nilesh J.; Schunkert, Heribert; Marrugat, Jaume; Elosua, Roberto; McPherson, Ruth; Farrall, Martin; Watkins, Hugh; Juang, Jyh-Ming J.; Hsiung, Chao A.; Lin, Shih-Yi; Wang, Jun-Sing; Tada, Hayato; Kawashiri, Masa-aki; Inazu, Akihiro; Yamagishi, Masakazu; Katsuya, Tomohiro; Nakashima, Eitaro; Nakatochi, Masahiro; Yamamoto, Ken; Yokota, Mitsuhiro; Momozawa, Yukihide; Rotter, Jerome I.; Rader, Daniel J.; Danesh, John; Ardissino, Diego; Gabriel, Stacey; Willer, Cristen J.; Abecasis, Goncalo R.; Saleheen, Danish; Kubo, Michiaki; Kato, Norihiro; Ida Chen, Yii-Der; Dewey, Frederick E.; Kathiresan, Sekar; Zekavat, Seyedeh M.; Murray, Michael F; Lander, Eric Steven; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology
Ovid Technologies (Wolters Kluwer Health)
Nomura, Akihiro et al. “Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease Novelty and Significance.” Circulation Research 121, 1 (May 2017): 81–88 © 2017 American Heart Association, Inc
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