Metabolic Effects of the Waist-To-Hip Ratio Associated Locus Are Related to Expression in Adipose Tissue.

locus has been shown to be associated with body fat distribution (FD), but neither the causal gene nor its role in metabolic diseases has been elucidated. We hypothesize that may act as the causal genes for FD-related SNPs (rs10195252 and rs6738627), and that they may be regulated by SNP to effect obesity-related metabolic traits. We genotyped rs10195252 and rs6738627 in 2860 subjects with metabolic phenotypes. In a subgroup of 560 subjects, we analyzed gene expression in paired visceral and subcutaneous adipose tissue (AT) samples. Mediation analyses were used to determine the causal relationship between SNPs, AT mRNA expression, and obesity-related traits. In vitro gene knockdown of was used to test their role in adipogenesis. Both gene expressions in AT are correlated with waist circumference. Visceral mRNA expression is associated with FPG and HbA1c. Both SNPs are associated with triglycerides, FPG, and leptin levels. Rs10195252 is associated with HbA1c and seems to be mediated by visceral AT mRNA expression. Our data support the role of the gene expression in body FD and its locus in metabolic sequelae: in particular, lipid metabolism and glucose homeostasis, which is likely mediated by AT transcript levels.