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The 3' Untranslated Region of the Lipoprotein Lipase Gene: Haplotype Structure and Association with Post-Heparin Plasma Lipase Activity

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (M.O.G) and Medical Genetics Institute (M.O.G., K.D.T., X.G., H.J.A., H.Y., J.I.R.), Cedars-Sinai Medical Center, Los Angeles, California 90048; the Lipid Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare Center (H.W.) and the Department of Medicine (H.W.), University of California, Los Angeles, California 90073; and Divisions of Endocrinology, Diabetes and Hypertension (M.J.Q., W.A.H.) and Cardiology (L.W.C.), Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90025

Address all correspondence and reprint requests to: Mark O. Goodarzi, M.D., Ph.D., Cedars-Sinai Medical Center Division of Endocrinology, Diabetes and Metabolism, 8700 Beverly Boulevard., Becker B-128, Los Angeles, California 90048. E-mail: mark.goodarzi{at}cshs.org.

Context: Haplotypes comprising six single nucleotide polymorphisms (SNPs) (intron 7 to intron 9) of the lipoprotein lipase (LPL) gene appear to influence risk for atherosclerosis and insulin resistance in Mexican-Americans.

Objective: Based on rodent studies, we hypothesized that these haplotypes are in linkage disequilibrium with functional variants in the 3' untranslated region of LPL, which is encoded by exon 10, and that these variants influence phenotype by altering LPL expression.

Design: We sequenced exon 10 in subjects with divergent insulin sensitivity and divergent haplotypes. We also sequenced the other common LPL haplotypes. Variants identified by sequencing were genotyped in a large, family-based population along with the six SNPs spanning intron 7 to intron 9. We tested the potential functional significance of variation in exon 10 by evaluating association of haplotypes with post-heparin plasma LPL activity.

Setting: The study took place within the general community, with the Mexican-American Coronary Artery Disease Project cohort.

Participants: Participants included 847 subjects from 163 families.

Main Outcome Measures: We determined LPL haplogenotype and post-heparin plasma LPL activity.

Results: Exon 10 sequencing identified 15 variants. Thirteen of these variants were genotyped in large-scale along with the six SNPs spanning intron 7 to intron 9. LPL haplotypes and their relative frequencies in Mexican-Americans were determined. The fourth most common haplotype based on 19 SNPs (haplotype 19-4) was associated with increased LPL activity as well as multiple phenotypes related to the metabolic syndrome.

Conclusions: These results support the possibility that variation in the 3' untranslated region of LPL affects LPL expression and activity, consequently influencing risk of atherosclerosis and insulin resistance, and provides important tools for further dissection of LPL regulation.

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