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Originally published In Press as doi:10.1194/jlr.M500042-JLR200 on June 16, 2005

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Journal of Lipid Research, Vol. 46, 1914-1922, September 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Higher order lipase gene association with plasma triglycerides

Muredach P. Reilly1,*, Andrea S. Foulkes{dagger}, Megan L. Wolfe* and Daniel J. Rader*

* Cardiovascular Division and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA
{dagger} Department of Biostatistics, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA

Published, JLR Papers in Press, June 16, 2005. DOI 10.1194/jlr.M500042-JLR200

1 To whom correspondence should be addressed. e-mail: muredach{at}spirit.gcrc.upenn.edu

Lipoprotein lipase, HL, and endothelial lipase (EL) are proteoglycan-bound enzymes that regulate plasma lipoprotein levels through coordinated triglyceride (TG) lipase and phospholipase activity. We hypothesized that single nucleotide polymorphisms (SNPs) in lipase genes would have higher order impact on plasma lipoproteins beyond the influence of individual SNPs. In a sample of asymptomatic Caucasian subjects (n = 738), we used a two-stage approach, first identifying groups of subjects with similar multilocus lipase genotypes and then characterizing the relationships between genotype groups and plasma lipids. Using complementary methods, including a permutation test procedure and a mixed-effects modeling approach, we found a higher order interaction between four SNPs in three lipase genes (EL 2,237 3' untranslated region, EL Thr111Ile, HL –514C/T, and LPL Hind III) and plasma TG levels. Subjects who were heterozygous for all four lipase SNPs had significantly higher plasma TG levels beyond the effect of individual lipase SNPs and environmental factors, even after correcting for multiple comparisons.

In conclusion, lipase genes had synergistic association with plasma TG beyond individual gene effects. Higher order multilocus genotype contributions to dyslipidemia and atherosclerotic cardiovascular disease need to be considered a priori because they may have an important effect even in the absence of significant main effects of the individual genes.

Supplementary key words lipoproteins • lipases • higher order gene interactions


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