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Diabetes 53:1385-1393, 2004
© 2004 by the American Diabetes Association, Inc.
Complex Haplotypes of the PGC-1
Gene Are Associated With Carbohydrate Metabolism and Type 2 Diabetes
1 Department of Laboratory Medicine, Landeskliniken and Paracelsus Private Medical University, Salzburg, Austria
2 Department of Internal Medicine, Landeskliniken and Paracelsus Private Medical University, Salzburg, Austria
3 Department of Neurology, Landeskliniken and Paracelsus Private Medical University, Salzburg, Austria
4 Department of Internal Medicine, Hospital Hallein, Hallein, Austria
Peroxisome proliferator–activated receptor coactivator-1
(PGC-1) is a transcriptional coactivator implicated in transcriptional programs of hepatic gluconeogenesis, oxidative phosphorylation, and insulin release by ß-cells. To study associations of the PGC-1 gene locus with carbohydrate metabolism and type 2 diabetes in humans, we identified several polymorphisms in the promoter region that were located in a haplotype block distinct from a second haplotype block containing part of intron 2 and extending beyond exon 13. Each block contained five common haplotypes. Oral glucose tolerance testing revealed associations of promoter haplotype combinations with 30- and 60-min postload plasma glucose levels, whereas haplotypes in both blocks were associated with indexes of ß-cell function. The associations of promoter haplotypes are supported by functional studies showing that some polymorphisms are located in transcription factor binding sites and affect transactivation in an allele-specific manner. By comparing patients with type 2 diabetes and control subjects, we observed borderline significant differences of four-loci haplotype distributions in the downstream haplotype block. Moreover, the haplotype that was associated with the strongest insulin response to glucose conferred the lowest risk of type 2 diabetes (P < 0.01). Thus, the PGC-1 gene locus influences carbohydrate metabolism and contributes to type 2 diabetes in the population studied.
Address correspondence and reprint requests to Wolfgang Patsch, MD, Department of Laboratory Medicine, LandesklinikenParacelsus Private Medical University Salzburg, Müllner Hauptstr. 48, A-5020 Austria. E-mail: w.patsch{at}lks.at
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