| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
Submitted on February 22, 2005
Accepted on May 24, 2005
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; 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; the Division of Endocrinology, Diabetes and Hypertension (M.J.Q., W.A.H.), Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; and the Division of Cardiology (L.W.C.), Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
* To whom correspondence should be addressed. E-mail: mark.goodarzi{at}cshs.org.
Context: Haplotypes comprising six 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 (UTR) 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: General community, the Mexican-American Coronary Artery Disease Project cohort.
Participants: 847 subjects from 163 families.
Main Outcome Measure(s): LPL haplogenotype; 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' UTR 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.
This article has been cited by other articles:
 |
|
 |
|
  M. O. Goodarzi, K. D. Taylor, X. Guo, J. E. Hokanson, S. M. Haffner, J. Cui, Y.-D. I. Chen, L. E. Wagenknecht, R. N. Bergman, and J. I. Rotter Haplotypes in the Lipoprotein Lipase Gene Influence Fasting Insulin and Discovery of a New Risk Haplotype J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 293 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rip, M. C. Nierman, C. J. Ross, J. W. Jukema, M. R. Hayden, J. J.P. Kastelein, E. S.G. Stroes, and J. A. Kuivenhoven Lipoprotein Lipase S447X: A Naturally Occurring Gain-of-Function Mutation Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1236 - 1245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Hegele, C. J.D. Ross, J. Twisk, J. A. Kuivenhoven, J. Rip, J. J. Kastelein, and M. R. Hayden Gene therapy with lipoprotein lipase variant S447X. Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): e25 - e25. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
