JAMA. 2017 Mar 7;317(9):937-946. doi: 10.1001/jama.2017.0972.
Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease.
Khera AV1, Won HH2, Peloso GM3, O'Dushlaine C4, Liu D5, Stitziel NO6, Natarajan P1, Nomura A1, Emdin CA1, Gupta N7, Borecki IB4, Asselta R8, Duga S8, Merlini PA9, Correa A10, Kessler T11, Wilson JG12, Bown MJ13, Hall AS14, Braund PS13, Carey DJ15, Murray MF15, Kirchner HL15, Leader JB15, Lavage DR15, Manus JN15, Hartzel DN15, Samani NJ13, Schunkert H16, Marrugat J17, Elosua R17, McPherson R18, Farrall M19, Watkins H19, Lander ES7, Rader DJ20, Danesh J21, Ardissino D22, Gabriel S7, Willer C23, Abecasis GR24, Saleheen D25, Dewey FE4, Kathiresan S1; Myocardial Infarction Genetics Consortium, DiscovEHR Study Group, CARDIoGRAM Exome Consortium, and Global Lipids Genetics Consortium.
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.
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.
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.
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 < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides.
Conclusions and Relevance:
The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.