Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease.
Nomura A., Won H-H., 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 J-MJ., Hsiung CA., Lin S-Y., Wang J-S., Tada H., Kawashiri M-A., 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 Y-D., 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 theCETPgene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at theCETPgene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of theCETPgene 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 ofCETPPTV carrier status with both plasma lipids and CHD. Among 58 469 participants withCETPgene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at theCETPgene. Compared with noncarriers, carriers of PTV atCETPhad 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).CETPPTV 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 atCETPdisplayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.