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

DiscovEHR Study Group, TAICHI Consortium

研究成果: Article

29 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)81-88
ページ数8
ジャーナルCirculation research
121
発行部数1
DOI
出版物ステータスPublished - 23-06-2017

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Cholesterol Ester Transfer Proteins
Coronary Disease
Genes
Proteins
Confidence Intervals
LDL Cholesterol
HDL Cholesterol
Case-Control Studies
Carrier Proteins
Triglycerides
Lipids
Protein Sequence Analysis
Risk Reduction Behavior
Exons

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

これを引用

DiscovEHR Study Group ; TAICHI Consortium. / Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease. :: Circulation research. 2017 ; 巻 121, 番号 1. pp. 81-88.
@article{e2ebd8613f1c43d4b1eca50a511b8a6f,
title = "Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease",
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.",
author = "{DiscovEHR Study Group} and {TAICHI Consortium} and Akihiro Nomura and Won, {Hong Hee} and Khera, {Amit V.} and Fumihiko Takeuchi and Kaoru Ito and Shane McCarthy and Emdin, {Connor A.} and Derek Klarin and Pradeep Natarajan and Zekavat, {Seyedeh M.} and Namrata Gupta and Peloso, {Gina M.} and Borecki, {Ingrid B.} and Teslovich, {Tanya M.} and Rosanna Asselta and Stefano Duga and Merlini, {Piera A.} and Adolfo Correa and Thorsten Kessler and Wilson, {James G.} and Bown, {Matthew J.} and Hall, {Alistair S.} and Braund, {Peter S.} and Carey, {David J.} and Murray, {Michael F.} and Kirchner, {H. Lester} and Leader, {Joseph B.} and Lavage, {Daniel R.} and Manus, {J. Neil} and Hartze, {Dustin N.} and Samani, {Nilesh J.} and Heribert Schunkert and Jaume Marrugat and Roberto Elosua and Ruth McPherson and Martin Farrall and Hugh Watkins and Juang, {Jyh Ming J.} and Hsiung, {Chao A.} and Lin, {Shih Yi} and Wang, {Jun Sing} and Hayato Tada and Kawashiri, {Masa Aki} and Akihiro Inazu and Masakazu Yamagishi and Tomohiro Katsuya and Eitaro Nakashima and Masahiro Nakatochi and Ken Yamamoto and Mitsuhiro Yokota",
year = "2017",
month = "6",
day = "23",
doi = "10.1161/CIRCRESAHA.117.311145",
language = "English",
volume = "121",
pages = "81--88",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease. / DiscovEHR Study Group; TAICHI Consortium.

:: Circulation research, 巻 121, 番号 1, 23.06.2017, p. 81-88.

研究成果: Article

TY - JOUR

T1 - Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease

AU - DiscovEHR Study Group

AU - TAICHI Consortium

AU - Nomura, Akihiro

AU - Won, Hong Hee

AU - Khera, Amit V.

AU - Takeuchi, Fumihiko

AU - Ito, Kaoru

AU - McCarthy, Shane

AU - Emdin, Connor A.

AU - Klarin, Derek

AU - Natarajan, Pradeep

AU - Zekavat, Seyedeh M.

AU - Gupta, Namrata

AU - Peloso, Gina M.

AU - Borecki, Ingrid B.

AU - Teslovich, Tanya M.

AU - Asselta, Rosanna

AU - Duga, Stefano

AU - Merlini, Piera A.

AU - Correa, Adolfo

AU - Kessler, Thorsten

AU - Wilson, James G.

AU - Bown, Matthew J.

AU - Hall, Alistair S.

AU - Braund, Peter S.

AU - Carey, David J.

AU - Murray, Michael F.

AU - Kirchner, H. Lester

AU - Leader, Joseph B.

AU - Lavage, Daniel R.

AU - Manus, J. Neil

AU - Hartze, Dustin N.

AU - Samani, Nilesh J.

AU - Schunkert, Heribert

AU - Marrugat, Jaume

AU - Elosua, Roberto

AU - McPherson, Ruth

AU - Farrall, Martin

AU - Watkins, Hugh

AU - Juang, Jyh Ming J.

AU - Hsiung, Chao A.

AU - Lin, Shih Yi

AU - Wang, Jun Sing

AU - Tada, Hayato

AU - Kawashiri, Masa Aki

AU - Inazu, Akihiro

AU - Yamagishi, Masakazu

AU - Katsuya, Tomohiro

AU - Nakashima, Eitaro

AU - Nakatochi, Masahiro

AU - Yamamoto, Ken

AU - Yokota, Mitsuhiro

PY - 2017/6/23

Y1 - 2017/6/23

N2 - 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.

AB - 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.

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