The 3' untranslated region of the lipoprotein lipase gene: haplotype structure and association with post-heparin plasma lipase activity.
BACKGROUND
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.


METHODS
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.


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


METHODS
Participants included 847 subjects from 163 families.


METHODS
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.
Goodarzi
Mark O
MO
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard., Becker B-128, Los Angeles, California 90048, USA. mark.goodarzi@cshs.org
Wong
Howard
H
Quiñones
Manuel J
MJ
Taylor
Kent D
KD
Guo
Xiuqing
X
Castellani
Lawrence W
LW
Antoine
Heath J
HJ
Yang
Huiying
H
Hsueh
Willa A
WA
Rotter
Jerome I
JI
D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D001161:Arteriosclerosis / Q000208:ethnology / Q000235:genetics*; D005091:Exons; D005260:Female; D006239:Haplotypes; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D007438:Introns; D015810:Linkage Disequilibrium; D008071:Lipoprotein Lipase / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D017058:Mexican Americans / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D020413:3' Untranslated Regions; D006493:Heparin; D008071:Lipoprotein Lipase