Evidence of an association between genetic variation of the coactivator PGC-1β and obesity

Background: Peroxisome proliferator activated receptor-gamma coactivator-1 beta ( PGC-1 beta) is a recently identified homologue of the tissue specific coactivator PGC-1 alpha, a coactivator of transcription factors such as the peroxisome proliferators activated receptors and nuclear respiratory factors. PGC-1 alpha is involved in adipogenesis, mitochondrial biogenesis, fatty acid beta oxidation, and hepatic gluconeogenesis. Methods: We studied variation in the coding region of human PPARGC1B in Danish whites and related these variations to the prevalence of obesity and type 2 diabetes in population based samples. Results: Twenty nucleotide variants were identified. In a study of 525 glucose tolerant subjects, the Ala203Pro and Val279Ile variants were in almost complete linkage disequilibrium (R-2 = 0.958). In a case control study of obesity involving a total of 7790 subjects, the 203Pro allele was significantly less frequent among obese participants ( p = 0.004; minor allele frequencies: normal weight subjects 8.1% (95% confidence interval: 7.5 to 8.8), overweight subjects 7.6% ( 7.0 to 8.3), obese subjects 6.5% (5.6 to 7.3)). In a case - control study involving 1433 patients with type 2 diabetes and 4935 glucose tolerant control subjects, none of the examined variants were associated with type 2 diabetes. Conclusions: Variation of PGC-1 beta may contribute to the pathogenesis of obesity, with a widespread Ala203 allele being a risk factor for the development of this common disorder.