Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance
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 pr...
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| Format: | Article |
| Publié: |
Ovid Technologies (Wolters Kluwer Health)
2018
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| Accès en ligne: | http://hdl.handle.net/1721.1/116679 |
| _version_ | 1826188310493528064 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering 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 |
| author_sort | Nomura, Akihiro |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T07:57:42Z |
| format | Article |
| id | mit-1721.1/116679 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T07:57:42Z |
| publishDate | 2018 |
| publisher | Ovid Technologies (Wolters Kluwer Health) |
| record_format | dspace |
| spelling | mit-1721.1/1166792022-09-30T01:17:52Z Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance 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 Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Zekavat, Seyedeh M. Murray, Michael F Lander, Eric Steven 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. 2018-06-28T17:47:06Z 2018-06-28T17:47:06Z 2017-05 2017-04 2018-06-28T13:04:05Z Article http://purl.org/eprint/type/JournalArticle 0009-7330 1524-4571 http://hdl.handle.net/1721.1/116679 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 http://dx.doi.org/10.1161/CIRCRESAHA.117.311145 Circulation Research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Ovid Technologies (Wolters Kluwer Health) PMC |
| spellingShingle | 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 Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance |
| title | Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance |
| title_full | Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance |
| title_fullStr | Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance |
| title_full_unstemmed | Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance |
| title_short | Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart DiseaseNovelty and Significance |
| title_sort | protein truncating variants at the cholesteryl ester transfer protein gene and risk for coronary heart diseasenovelty and significance |
| url | http://hdl.handle.net/1721.1/116679 |
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