DUSP1 Gene Polymorphisms Are Associated with Obesity-Related Metabolic Complications among Severely Obese Patients and Impact on Gene Methylation and Expression
The DUSP1 gene encodes a member of the dual-specificity phosphatase family previously identified as being differentially expressed in visceral adipose tissue (VAT) of severely obese men with versus without the metabolic syndrome. Objective. To test the association between DUSP1 polymorphisms, obesity-related metabolic complications, gene methylation, and expression levels in VAT. 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 lower HDL-cholesterol levels (HDL-C; ), and homozygotes for the minor allele of rs13184134 and rs7702178 had increased fasting glucose levels ( 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 polymorphisms modulate plasma glucose and HDL-C levels in obese patients possibly through alterations of DNA methylation and gene expression levels. 1. Introduction Obesity in adults and in adolescents significantly increases the risk for several chronic diseases including cardiovascular diseases (CVD) and type 2 diabetes (T2D) [1, 2]. Excess accumulation of fat inside the abdominal cavity (visceral adipose tissue: VAT) is associated with altered insulin sensitivity, blood pressure (BP), and plasma lipid profile [3, 4]. Clustering of CVD risk factors including accumulation of abdominal fat, impaired glucose tolerance, dyslipidemia, and hypertension defines the metabolic syndrome (MetS) [5]. Interindividual variability in obesity-related complications is observed. Not all obese individuals develop the MetS, and as much as 20% of the obese population could have normal metabolic parameters even in the presence of extensive adipose tissue accumulation [6]. Our knowledge of the factors involved in the etiology of obesity-related metabolic disturbances, either alone or clustered under the MetS designation, remains largely incomplete, with evidence pointing to a potential implication of immunity and inflammatory processes as well as oxidative stress [7, 8]. There is also strong evidence for genetic components in the development of these perturbations [9]. In a previous
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