title: Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes.
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.
authors.affiliation: Department of Laboratory Medicine, Landeskliniken and Paracelsus Private Medical University Salzburg, Müllner Hauptstrasse 48, A-5020 Salzburg, Austria.
authors.forename: Hannes
authors.initials: H
authors.lastname: Oberkofler
authors.forename: Veronika
authors.initials: V
authors.lastname: Linnemayr
authors.forename: Raimund
authors.initials: R
authors.lastname: Weitgasser
authors.forename: Kerstin
authors.initials: K
authors.lastname: Klein
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Xie
authors.forename: Bernhard
authors.initials: B
authors.lastname: Iglseder
authors.forename: Franz
authors.initials: F
authors.lastname: Krempler
authors.forename: Bernhard
authors.initials: B
authors.lastname: Paulweber
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Patsch
mesh_terms: D000368:Aged; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D006239:Haplotypes; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D006360:Heat-Shock Proteins; D007328:Insulin; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors