Higher-order lipase gene association with plasma triglycerides

Muredach P. Reilly, Andrea S. Foulkes, Megan L. Wolfe, and Daniel J. Rader

Medicine Dept., University of Pennsylvania, Philadelphia, PA 19104-6160

Corresponding Author: muredach{at}spirit.gcrc.upenn.edu

Lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL) are proteoglycan-bound enzymes that regulate plasma lipoprotein levels through coordinate triglyceride (TG) lipase and phospholipase activity. We hypothesized that 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 multi-locus lipase genotypes and then characterizing the relationships between genotype groups and plasma lipids. Using complementary methods, including a permutation test procedure and mixed effects modeling approach, we found a higher-order interaction between four SNPs in three lipase genes (EL 2237 3'UTR, EL Thr111Ile, HL -514C/T and LPL HindIII) 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 multi-locus genotype contributions to dyslipidemia and atherosclerotic cardiovascular disease need to be considered a priori because they may have an important impact even in the absence of significant main effects of the individual genes.

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