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.
| Original language | English |
|---|---|
| Pages (from-to) | 81-88 |
| Number of pages | 8 |
| Journal | Circulation Research |
| Volume | 121 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 23-06-2017 |
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All Science Journal Classification (ASJC) codes
- Physiology
- Cardiology and Cardiovascular Medicine
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Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease. / DiscovEHR Study Group; TAICHI Consortium.
In: Circulation Research, Vol. 121, No. 1, 23.06.2017, p. 81-88.Research output: Contribution to journal › 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 - Kubo, Michiaki
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.
UR - http://www.scopus.com/inward/record.url?scp=85020786942&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020786942&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.117.311145
DO - 10.1161/CIRCRESAHA.117.311145
M3 - Article
C2 - 28506971
AN - SCOPUS:85020786942
VL - 121
SP - 81
EP - 88
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 1
ER -