Dataset Information

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

ABSTRACT: 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.To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD.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).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.

SUBMITTER: Nomura A

PROVIDER: S-EPMC5523940 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Nomura Akihiro A Won Hong-Hee HH Khera Amit V AV Takeuchi Fumihiko F Ito Kaoru K McCarthy Shane S Emdin Connor A CA Klarin Derek D Natarajan Pradeep P Zekavat Seyedeh M SM Gupta Namrata N Peloso Gina M GM Borecki Ingrid B IB Teslovich Tanya M TM Asselta Rosanna R Duga Stefano S Merlini Piera A PA Correa Adolfo A Kessler Thorsten T Wilson James G JG Bown Matthew J MJ Hall Alistair S AS Braund Peter S PS Carey David J DJ Murray Michael F MF Kirchner H Lester HL Leader Joseph B JB Lavage Daniel R DR Manus J Neil JN Hartze Dustin N DN Samani Nilesh J NJ Schunkert Heribert H Marrugat Jaume J Elosua Roberto R McPherson Ruth R Farrall Martin M Watkins Hugh H Juang Jyh-Ming J JJ Hsiung Chao A CA Lin Shih-Yi SY Wang Jun-Sing JS Tada Hayato H Kawashiri Masa-Aki MA Inazu Akihiro A Yamagishi Masakazu M Katsuya Tomohiro T Nakashima Eitaro E Nakatochi Masahiro M Yamamoto Ken K Yokota Mitsuhiro M Momozawa Yukihide Y Rotter Jerome I JI Lander Eric S ES Rader Daniel J DJ Danesh John J Ardissino Diego D Gabriel Stacey S Willer Cristen J CJ Abecasis Goncalo R GR Saleheen Danish D Kubo Michiaki M Kato Norihiro N Ida Chen Yii-Der YD Dewey Frederick E FE Kathiresan Sekar S

Circulation research 20170515 1

<h4>Rationale</h4>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 <i>CETP</i> gene may provide insight into the efficacy of CETP inhibition.<h4>Objective</h4>To test whether protein-truncating variants (PTVs) at the <i>CETP</i> gene were associated with plasma lipid levels and CHD.<h4>Methods and results</h4>We sequenced the exons of the <i>CETP</i> gene ...[more]

PMID: 28506971

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Project description:AimsThis meta-analysis aimed to assess the association of the polymorphisms of cholesterol ester transfer protein (CETP) rs708272 (G>A), rs5882 (G>A), rs1800775 (C>A), rs4783961 (G>A), rs247616 (C>T), rs5883 (C>T), rs1800776 (C>A), and rs1532624 (C>A) with coronary artery disease (CAD) and the related underlying mechanisms.MethodsA comprehensive search was performed using five databases such as PubMed, EMBASE, Web of Science, Cochrane Library and Scopus to obtain the appropriate articles. The quality of the included studies was assessed by the Newcastle-Ottawa Scale. The statistical analysis of the data was performed using STATA 17.0 software. The association between CETP gene polymorphisms and risk of CAD was estimated using the pooled odds ratio (OR) and 95% confidence interval (95% CI). The association of CETP gene polymorphisms with lipids and with CETP levels was assessed using the pooled standardized mean difference and corresponding 95% CI. P < 0.05 was considered statistically significant.ResultsA total of 70 case-control studies with 30,619 cases and 31,836 controls from 46 articles were included. The results showed the CETP rs708272 polymorphism was significantly associated with a reduced risk of CAD under the allele model (OR = 0.846, P < 0.001), the dominant model (OR = 0.838, P < 0.001) and the recessive model (OR = 0.758, P < 0.001). AA genotype and GA genotype corresponded to higher high-density lipoprotein cholesterol (HDL-C) concentrations in the blood compared with GG genotype across the studied groups (all P < 0.05). The CETP rs5882 and rs1800775 polymorphisms were not significantly associated with CAD under the allele model (P = 0.802, P = 0.392), the dominant model (P = 0.556, P = 0.183) and the recessive model (P = 0.429, P = 0.551). Similarly, the other mentioned gene polymorphisms were not significantly associated with CAD under the three genetic models.ConclusionsThe CETP rs708272 polymorphism shows a significant association with CAD, and the carriers of the allele A are associated with a lower risk of CAD and higher HDL-C concentrations in the blood compared to the non-carriers. The CETP rs5882, rs1800775, rs4783961, rs247616, rs5883, rs1800776, and rs1532624 are not significantly associated with CAD.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023432865, identifier: CRD42023432865.

Dataset Information

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

Publications

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

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