Association of rare and common variation in the lipoprotein lipase gene with coronary artery disease

Amit V. Khera, Hong Hee Won, Gina M. Peloso, Colm O'Dushlaine, Dajiang Liu, Nathan O. Stitziel, Pradeep Natarajan, Akihiro Nomura, Connor A. Emdin, Namrata Gupta, Ingrid B. Borecki, Rosanna Asselta, Stefano Duga, Piera Angelica Merlini, Adolfo Correa, Thorsten Kessler, James G. Wilson, Matthew J. Bown, Alistair S. Hall, Peter S. BraundDavid J. Carey, Michael F. Murray, H. Lester Kirchner, Joseph B. Leader, Daniel R. Lavage, J. Neil Manus, Dustin N. Hartzel, Nilesh J. Samani, Heribert Schunkert, Jaume Marrugat, Roberto Elosua, Ruth McPherson, Martin Farrall, Hugh Watkin, Eric S. Lander, Daniel J. Rader, John Danesh, Diego Ardissino, Stacey Gabriel, Cristen Willer, Gonçalo R. Abecasis, Danish Saleheen, Frederick E. Dewey, Sekar Kathiresan

Research output: Contribution to journalArticle

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Abstract

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, LPLwas 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 (19.6mg/dL; 95%CI, 4.6-34.6mg/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 .

Original languageEnglish (US)
Pages (from-to)937-946
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume317
Issue number9
DOIs
StatePublished - Mar 7 2017

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Khera, A. V., Won, H. H., Peloso, G. M., O'Dushlaine, C., Liu, D., Stitziel, N. O., Natarajan, P., Nomura, A., Emdin, C. A., Gupta, N., Borecki, I. B., Asselta, R., Duga, S., Merlini, P. A., Correa, A., Kessler, T., Wilson, J. G., Bown, M. J., Hall, A. S., ... Kathiresan, S. (2017). Association of rare and common variation in the lipoprotein lipase gene with coronary artery disease. JAMA - Journal of the American Medical Association, 317(9), 937-946. https://doi.org/10.1001/jama.2017.0972