Nature Genetics
26, 76 - 80 (2000)
doi:10.1038/79216
The common PPAR Pro12Ala polymorphism is associated with decreased risk of type 2 diabetesDavid Altshuler1, 2, 3, 10, Joel N. Hirschhorn1, 3, 4, 10, Mia Klannemark5, Cecilia M. Lindgren1, 5, Marie-Claude Vohl6, James Nemesh1, Charles R. Lane1, Stephen F. Schaffner1, Stacey Bolk1, Carl Brewer6, Tiinamaija Tuomi5, 7, Daniel Gaudet8, Thomas J. Hudson1, 6, Mark Daly1, Leif Groop5
& Eric S. Lander1, 91
Whitehead Institute/MIT Center for Genome Research, Cambridge, Massachusetts, USA. 2
Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. 3
Harvard Medical School, Boston, Massachusetts, USA. 4
Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA. 5
Department of Endocrinology, Wallenberg Laboratory, Malmö University Hospital, University of Lund, Malmö, Sweden. 6
Montreal Genome Centre, McGill University Health Centre Research Institute, Montréal, Canada. 7
Department of Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland. 8
Chicoutimi Hospital, Chicoutimi, Quebec, Canada. 9
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 10
These authors contributed equally to this report.
Correspondence should be addressed to Eric S. Lander lander@genome.wi.mit.edu)Genetic association studies are viewed as problematic and plagued by irreproducibility1. Many associations have been reported for type 2 diabetes2,
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- (PPAR) 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 PPAR. An initial study found a threefold effect12, but four of five subsequent publications18,
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 PPAR 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.
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