Visceral fat mass is a strong and independent predictor of obesity-related disorders. To date, little is known about the genetic determinants of regional body fat distribution in humans. As candidates of regional fat distribution, we investigated the fat mass- and obesity-associated gene, the peroxisome proliferator-activated receptor-delta gene, and the retinoic acid. receptor responder 2 (RARRES2) gene. We studied whether genetic variation within these genes contributes to the development of disproportionate visceral obesity and obesity-related traits, such as insulin resistance and beta-cell dysfunction. We genotyped 337 subjects with an increased risk for type 2 diabetes mellitus for tagging single nucleotide polymorphisms (SNPs) in the 3 genes and performed association analyses with anthropometric data and parameters of insulin sensitivity and beta-cell function. All subjects underwent an oral glucose tolerance test; a subset was additionally characterized by a hyperinsulinemic-euglycemic clamp. Body fat distribution was assessed by nuclear magnetic resonance imaging. The fat mass- and obesity-associated gene SNP rs8050136 was nominally associated with body mass index (P = .0130), but not with body fat distribution, after appropriate adjustment. Magnetic resonance imaging-quantified visceral fat mass was significantly associated with RARRES2 SNP rs17173608 and nominally associated with RARRES2 SNP rs10278590 in nonobese subjects (P = .0002 and P =,0423, respectively), with carriers of the minor alleles displaying lower visceral adipose tissue mass. Besides, the minor allele of SNP rs17173608 was nominally associated with a lower waist-to-hip ratio (P = .0295). In obese subjects, these associations were not detected. No associations were found between the peroxisome proliferator-activated receptor-delta gene and measures of whole-body adiposity and of body fat distribution. All SNPs were associated neither with insulin sensitivity nor with insulin secretion. Common genetic variation within RARRES2 is associated with increased visceral fat mass in nonobese subjects. In generalized obesity, this genetic effect may be masked by the close association between whole-body obesity and visceral fat mass. (C) 2009 Elsevier Inc. All rights reserved.
