Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease.
Khera AV., Won H-H., Peloso GM., O'Dushlaine C., Liu D., Stitziel NO., Natarajan P., Nomura A., Emdin CA., Gupta N., Borecki IB., 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., Hartzel DN., Samani NJ., Schunkert H., Marrugat J., Elosua R., McPherson R., Farrall M., Watkins H., Lander ES., Rader DJ., Danesh J., Ardissino D., Gabriel S., Willer C., Abecasis GR., Saleheen D., Dewey FE., Kathiresan S., Myocardial Infarction Genetics Consortium, DiscovEHR Study Group, CARDIoGRAM Exome Consortium, and Global Lipids Genetics Consortium None.
Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P