ABSTRACT
BACKGROUND: Inflammation plays a central role in chronic diseases occurring in the contemporary society. The health benefits of omega-3 (n-3) fatty acids (FAs), mostly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been reported. However, their mechanisms of action are poorly understood. We explored dose and time effects of EPA, DHA, and a mixture of EPA + DHA on the expression of inflammatory genes in stimulated macrophages. METHODS: Lipopolysaccharide was used to stimulate human THP-1 macrophages. Cells were incubated in different conditions in the presence of n-3 FAs and LPS, and mRNA levels of inflammatory genes were measured by real-time PCR. Cytokine levels in culture media were measured. RESULTS: The mixture of EPA + DHA had a more effective inhibitory effect than either DHA or EPA alone, DHA being more potent than EPA. For both EPA and DHA, 75 µM of FAs had a more important anti-inflammatory effect than 10 or 50 µM. For gene expression, EPA had the greater action during the post-incubation (after LPS treatment) condition while DHA and EPA + DHA were more potent during the co-incubation (n-3 FAs and LPS). Cytokine concentrations decreased more markedly in the co-incubation condition. CONCLUSIONS: These results suggest that in stimulated macrophages, expression levels of genes involved in inflammation are influenced by the dose, the type of n-3 FAs, and the time of incubation.
ABSTRACT
OBJECTIVE: A novel single-nucleotide polymorphism (SNP) associated with morbid obesity was recently identified by exome sequencing. The purpose of this study was to follow up this low-frequency coding SNP located within the SYPL2 locus and associated with body mass index in order to reveal novel associations with obesity-related traits. METHODS: The body mass index-associated SNP (rs62623713 A>G [chr1:109476817/hg19]) and two tagging SNPs within the SYPL2 locus, rs9661614 T>C (chr1:109479215) and rs485660 G>A (chr1:109480810), were genotyped in the obesity (n = 3,017) and the infogene (n = 676) cohorts, which were further combined, leading to a larger cohort of 3,693 individuals. Association testing was performed by general linear models in the obesity cohort and validated by joint analysis in the combined cohort. RESULTS: rs9661614 and rs485660 were significantly associated with hip circumference (HC) in the obesity cohort, with heterozygotes exhibiting a significantly lower HC. These results were validated by joint analysis for rs9661614 (false discovery rate [FDR]-corrected P = 7.5 × 10-4) and, to a lesser extent, for rs485660 (FDR corrected P = 3.9 × 10-2). The association with HC remained significant for rs9661614 when tested independently in women (FDR-corrected P = 1.7 × 10-2), but not for rs485660 (FDR-corrected P = 0.2). Both associations were absent in men. CONCLUSIONS: This study reveals strong evidence for a novel association between rs9661614 (T>C) and HC in women, which likely reflects a preferential association of SYPL2 to a gynoid profile of fat distribution. The study findings support a clinical significance of SYPL2 worth considering when assessing risk factors associated with obesity.
ABSTRACT
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; P = 0.01), and homozygotes for the minor 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 polymorphisms modulate plasma glucose and HDL-C levels in obese patients possibly through alterations of DNA methylation and gene expression levels.
