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The SNP variant rs2943650 near  IRS1  gene locus was previously associated with decreased body fat and  IRS1  gene expression as well as an adverse metabolic profile in humans. Here, we hypothesize that these effects may be mediated by an interplay with epigenetic alterations. We measured  IRS1  promoter DNA methylation and mRNA expression in paired human subcutaneous and omental visceral adipose tissue samples (SAT and OVAT) from 146 and 41 individuals, respectively. Genotyping of rs2943650 was performed in all individuals ( N  = 146). We observed a significantly higher  IRS1  promoter DNA methylation in OVAT compared to SAT (N = 146,  P  = 8.0 × 10 −6 ), while expression levels show the opposite effect direction (N = 41,  P  = 0.011). OVAT and SAT methylation correlated negatively with  IRS1  gene expression in obese subjects (N = 16,  P  = 0.007 and  P  = 0.010). The major T-allele is related to increased DNA methylation in OVAT (N = 146,  P  = 0.019). Finally, DNA methylation and gene expression in OVAT correlated with anthropometric traits (waist- circumference waist-to-hip ratio) and parameters of glucose metabolism in obese individuals. Our data suggest that the association between rs2943650 near the  IRS1  gene locus with clinically relevant variables may at least be modulated by changes in DNA methylation that translates into altered  IRS1  gene expression.

IRS1 DNA promoter methylation and expression in human adipose tissue are related to fat distribution and metabolic traits