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

• Published in: Circulation research Vol. 121; no. 1; pp. 81 - 88
• Main Authors: Nomura, Akihiro, Won, Hong-Hee, Khera, Amit V., Takeuchi, Fumihiko, Ito, Kaoru, McCarthy, Shane, Emdin, Connor A., Klarin, Derek, Natarajan, Pradeep, Zekavat, Seyedeh M., 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., Murray, Michael F., 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., Lander, Eric S., 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
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins Ovid Technologies 23.06.2017
• Subjects: Adult; Aged; Cardiovascular disease; Case-Control Studies; CETP gene; Cholesterol; Cholesterol Ester Transfer Proteins - blood; Cholesterol Ester Transfer Proteins - genetics; Cholesteryl ester transfer protein; Confidence intervals; Coronary artery disease; Coronary Disease - blood; Coronary Disease - diagnosis; Coronary Disease - genetics; Exons; Female; Genetic Variation - genetics; Health risk assessment; Heart diseases; Humans; Lipids; Low density lipoprotein; Male; Middle Aged; Nucleotide sequence; Proteins; Risk Factors; Triglycerides; coronary disease; lipids; cholesteryl ester transfer protein; case-control studies
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.117.311145

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 gene may provide insight into the efficacy of CETP inhibition. To test whether protein-truncating variants (PTVs) at the gene were associated with plasma lipid levels and CHD. We sequenced the exons of the 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 PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the gene. Compared with noncarriers, carriers of PTV at had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; <1.0×10 ), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; =0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; =0.043). PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; =5.1×10 ). Compared with noncarriers, carriers of PTV at displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.