Association of Uncoupling Protein-1 Haplotypes with Body Fat Area

Obesity is a major cause of morbidity and mortality and is associated with risks for type 2 diabetes mellitus, heart disease, metabolic syndrome, hypertension, stroke, and certain forms of cancer. The glutamate decarboxylase 2 (GAD2), insulin-induced gene 2 (INSIG2), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), melanocortin 4 receptor (MC4R), fresh touring origination (FTO), and uncoupling protein-1 (UCP-1) genes have been investigated for their association with obesity.Since the A-3826G SNP in the UCP-1 gene was first shown to be the key genetic determinant of obesity and body fat accumulation, many studies have been performed in various populations to measure the association of the G allele of this SNP with obesity phenotypes. The association of the A-3826G SNP with obesity has been controversial, however, suggesting that one SNP does not sufficiently explain the effects of genomic variation on body fat accumulation.In this study, 9 SNPs were newly identified in the 5’-flanking region of the UCP-1 gene by direct sequencing of genomic DNA from 21 Korean subjects, and 6 haplotypes were obtained by SNP genotyping and haplotype reconstruction. According to our haplotype analysis, ht2 of the G allele of A-3826G, was significantly associated with overall fat measures after age and body weight were adjusted. Ht6 of the A allele of A-3826G, was significantly linked to reduced fat accumulation. These results provide an explanation for the controversies that have been reported in many obesity association studies and suggest that haplotype associations between polymorphic loci and neighbor loci that harbor functional sequence variants can be exploited to identify disease-predisposing alleles.