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.
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.
Authors: K Hirano; S Yamashita; N Nakajima; T Arai; T Maruyama; Y Yoshida; M Ishigami; N Sakai; K Kameda-Takemura; Y Matsuzawa Journal: Arterioscler Thromb Vasc Biol Date: 1997-06 Impact factor: 8.311
Authors: A Inazu; M L Brown; C B Hesler; L B Agellon; J Koizumi; K Takata; Y Maruhama; H Mabuchi; A R Tall Journal: N Engl J Med Date: 1990-11-01 Impact factor: 91.245
Authors: Amit V Khera; Hong-Hee Won; Gina M Peloso; Kim S Lawson; Traci M Bartz; Xuan Deng; Elisabeth M van Leeuwen; Pradeep Natarajan; Connor A Emdin; Alexander G Bick; Alanna C Morrison; Jennifer A Brody; Namrata Gupta; Akihiro Nomura; Thorsten Kessler; Stefano Duga; Joshua C Bis; Cornelia M van Duijn; L Adrienne Cupples; Bruce Psaty; Daniel J Rader; John Danesh; Heribert Schunkert; Ruth McPherson; Martin Farrall; Hugh Watkins; Eric Lander; James G Wilson; Adolfo Correa; Eric Boerwinkle; Piera Angelica Merlini; Diego Ardissino; Danish Saleheen; Stacey Gabriel; Sekar Kathiresan Journal: J Am Coll Cardiol Date: 2016-04-03 Impact factor: 24.094
Authors: Nathan O Stitziel; Hong-Hee Won; Alanna C Morrison; Gina M Peloso; Ron Do; Leslie A Lange; Pierre Fontanillas; Namrata Gupta; Stefano Duga; Anuj Goel; Martin Farrall; Danish Saleheen; Paola Ferrario; Inke König; Rosanna Asselta; Piera A Merlini; Nicola Marziliano; Maria Francesca Notarangelo; Ursula Schick; Paul Auer; Themistocles L Assimes; Muredach Reilly; Robert Wilensky; Daniel J Rader; G Kees Hovingh; Thomas Meitinger; Thorsten Kessler; Adnan Kastrati; Karl-Ludwig Laugwitz; David Siscovick; Jerome I Rotter; Stanely L Hazen; Russell Tracy; Sharon Cresci; John Spertus; Rebecca Jackson; Stephen M Schwartz; Pradeep Natarajan; Jacy Crosby; Donna Muzny; Christie Ballantyne; Stephen S Rich; Christopher J O'Donnell; Goncalo Abecasis; Shamil Sunaev; Deborah A Nickerson; Julie E Buring; Paul M Ridker; Daniel I Chasman; Erin Austin; Iftikhar J Kullo; Peter E Weeke; Christian M Shaffer; Lisa A Bastarache; Joshua C Denny; Dan M Roden; Colin Palmer; Panos Deloukas; Dan-Yu Lin; Zheng-zheng Tang; Jeanette Erdmann; Heribert Schunkert; John Danesh; Jaume Marrugat; Roberto Elosua; Diego Ardissino; Ruth McPherson; Hugh Watkins; Alex P Reiner; James G Wilson; David Altshuler; Richard A Gibbs; Eric S Lander; Eric Boerwinkle; Stacey Gabriel; Sekar Kathiresan Journal: N Engl J Med Date: 2014-11-12 Impact factor: 91.245
Authors: Robert S Rosenson; H Bryan Brewer; Philip J Barter; Johan L M Björkegren; M John Chapman; Daniel Gaudet; Daniel Seung Kim; Eric Niesor; Kerry-Anne Rye; Frank M Sacks; Jean-Claude Tardif; Robert A Hegele Journal: Nat Rev Cardiol Date: 2017-08-10 Impact factor: 32.419