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The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes

The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes Genetic association studies are viewed as problematic and plagued by irreproducibility 1 . Many associations have been reported for type 2 diabetes 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 , but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ (PPARγ) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (∼85% frequency). Moreover, our results resolve a controversy about common variation in PPARγ. An initial study found a threefold effect 12 , but four of five subsequent publications 18,19,20,21,22 failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARγ in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk—influencing as much as 25% of type 2 diabetes in the general population. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Genetics Springer Journals

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References (40)

Publisher
Springer Journals
Copyright
Copyright © 2000 by Nature America Inc.
Subject
Biomedicine; Biomedicine, general; Human Genetics; Cancer Research; Agriculture; Gene Function; Animal Genetics and Genomics
ISSN
1061-4036
eISSN
1546-1718
DOI
10.1038/79216
Publisher site
See Article on Publisher Site

Abstract

Genetic association studies are viewed as problematic and plagued by irreproducibility 1 . Many associations have been reported for type 2 diabetes 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 , but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ (PPARγ) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (∼85% frequency). Moreover, our results resolve a controversy about common variation in PPARγ. An initial study found a threefold effect 12 , but four of five subsequent publications 18,19,20,21,22 failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARγ in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk—influencing as much as 25% of type 2 diabetes in the general population.

Journal

Nature GeneticsSpringer Journals

Published: Sep 1, 2000

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