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Sci Rep. 2017 Sep 28;7(1):12369. doi: 10.1038/s41598-017-12393-5.

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

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IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
Department of Clinical and Molecular Biology and Akershus University Hospital, University of Oslo, Lørenskog, Norway.
Interdisciplinary Centre for Bioinformatics, University of Leipzig, Leipzig, Germany.
Department of Computer Science, University of Leipzig, Leipzig, Germany.
Department of Clinical Sciences, Skåne University Hospital, Malmö, Sweden.
Department of Medicine, University of Leipzig, Leipzig, Germany.
Department of Surgery, University of Leipzig, Leipzig, Germany.
Clinic of Visceral Surgery, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
Municipal Clinic Dresden-Neustadt, Dresden, Germany.
IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
University of Oslo, Institute of Clinical Medicine, Department of Clinical and Molecular Biology; Akershus University Hospital, 1478, Lørenskog, Norway.


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.

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