DUSP1 Gene Polymorphisms Are Associated with Obesity-Related Metabolic Complications among Severely Obese Patients and Impact on Gene Methylation and Expression.

TheDUSP1 gene encodes a member of the dual-specificity phosphatase family previously identified as being differentially expressed in visceral adipose tissue (VAT) of severely obesemen with versus without the metabolic syndrome. Objective. To test the association betweenDUSP1 polymorphisms, obesity-relatedmetabolic complications, gene methylation, and expression levels inVAT. Methods. The DUSP1 locus and promoter region were sequenced in 25 individuals. SNPs were tested for association with obesity-related complications in a cohort of more than 1900 severely obese individuals. The impact of SNPs on methylation levels of 36 CpG sites and correlations between DNA methylation and gene expression levels in VAT were computed in a subset of 14 samples. Results. Heterozygotes for rs881150 had lowerHDL-cholesterol levels (HDL-C; P= 0.01), and homozygotes for theminor allele of rs13184134 and rs7702178 had increased fasting glucose levels (P= 0.04 and 0.01, resp.). rs881150 was associated with methylation levels of CpG sites located ~1250 bp upstream the transcription start site. Methylation levels of 4 CpG sites were inversely correlated with DUSP1 gene expression. Conclusion. These results suggest that DUSP1 polymorphismsmodulate plasma glucose andHDL-C levels in obese patients possibly through alterations of DNA methylation and gene expression levels. [ABSTRACT FROM AUTHOR]