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 JJ., Hsiung CA., Lin SY., Wang JS., Tada H., Kawashiri MA., 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., Ida Chen YD., Dewey FE., Kathiresan S.
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.