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- Title
Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes.
- Authors
Oberkofler, Hannes; Linnemayr, Veronika; Weitgasser, Raimund; Klein, Kerstin; Xie, Mingqiang; Iglseder, Bernhard; Krempler, Franz; Paulweber, Bernhard; Patsch, Wolfgang
- Abstract
Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator implicated in transcriptional programs of hepatic gluconeogenesis, oxidative phosphorylation, and insulin release by beta-cells. To study associations of the PGC-1alpha 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 beta-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-1alpha gene locus influences carbohydrate metabolism and contributes to type 2 diabetes in the population studied.
- Subjects
HAPLOIDY; GENES; CARBOHYDRATE metabolism; TYPE 2 diabetes; INSULIN resistance; PANCREATIC beta cells; PEROXISOMES; GENETICS
- Publication
Diabetes, 2004, Vol 53, Issue 5, p1385
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.53.5.1385