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<1.0x10(-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=5.1x10(-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.

Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease / Nomura, A; Won, Hh; Khera, Av; Takeuchi, F; Ito, K; Mccarthy, S; Emdin, Ca; Klarin, D; Natarajan, P; Zekavat, Sm; Gupta, N; Peloso, Gm; Borecki, Ib; Teslovich, Tm; Asselta, R; Duga, S; Merlini, Pa; Correa, A; Kessler, T; Wilson, Jg; Bown, Mj; Hall, As; Braund, Ps; Carey, Dj; Murray, Mf; Kirchner, Hl; Leader, Jb; Lavage, Dr; Manus, Jn; Hartze, Dn; Samani, Nj; Schunkert, H; Marrugat, J; Elosua, R; Mcpherson, R; Farrall, M; Watkins, H; Juang, Jmj; Hsiung, Ca; Lin, Sy; Wang, Js; Tada, H; Kawashiri, M; Inazu, A; Yamagishi, M; Katsuya, T; Nakashima, E; Nakatochi, M; Yamamoto, K; Yokota, M; Momozawa, Y; Rotter, Ji; Lander, Es; Rader, Dj; Danesh, J; Ardissino, D; Gabriel, S; Willer, Cj; Abecasis, Gr; Saleheen, D; Kubo, M; Kato, N; Chen, Ydi; Dewey, Fe; Kathiresan, S. - In: CIRCULATION RESEARCH. - ISSN 0009-7330. - 121:1(2017), pp. 81-88. [10.1161/CIRCRESAHA.117.311145]

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

Ardissino D;
2017-01-01

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<1.0x10(-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=5.1x10(-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.
Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease / Nomura, A; Won, Hh; Khera, Av; Takeuchi, F; Ito, K; Mccarthy, S; Emdin, Ca; Klarin, D; Natarajan, P; Zekavat, Sm; Gupta, N; Peloso, Gm; Borecki, Ib; Teslovich, Tm; Asselta, R; Duga, S; Merlini, Pa; Correa, A; Kessler, T; Wilson, Jg; Bown, Mj; Hall, As; Braund, Ps; Carey, Dj; Murray, Mf; Kirchner, Hl; Leader, Jb; Lavage, Dr; Manus, Jn; Hartze, Dn; Samani, Nj; Schunkert, H; Marrugat, J; Elosua, R; Mcpherson, R; Farrall, M; Watkins, H; Juang, Jmj; Hsiung, Ca; Lin, Sy; Wang, Js; Tada, H; Kawashiri, M; Inazu, A; Yamagishi, M; Katsuya, T; Nakashima, E; Nakatochi, M; Yamamoto, K; Yokota, M; Momozawa, Y; Rotter, Ji; Lander, Es; Rader, Dj; Danesh, J; Ardissino, D; Gabriel, S; Willer, Cj; Abecasis, Gr; Saleheen, D; Kubo, M; Kato, N; Chen, Ydi; Dewey, Fe; Kathiresan, S. - In: CIRCULATION RESEARCH. - ISSN 0009-7330. - 121:1(2017), pp. 81-88. [10.1161/CIRCRESAHA.117.311145]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2883522
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