Dietary supplementation with fish oil modifies the ability of human monocytes to induce an inflammatory response.

Monocytes/macrophages are key orchestrators of inflammation and are involved in the pathogenesis of chronic inflammatory disorders, including atherosclerosis. (n-3) Fatty acids, found in fish oil, have been shown to have protective effects in such disorders. To investigate possible modes of action, we used a monocyte:endothelial cell (EC) coculture model to investigate the pro-inflammatory potential of monocytes. Monocytes were isolated from the blood of donors with peripheral arterial disease (PAD) or control donors, before and after a 12-wk supplementation of their diet with fish oil. The monocytes were cultured with human umbilical vein EC (HUVEC) for 24 h, after which the ability of the HUVEC to recruit flowing neutrophils was tested. Monocytes from either group of donors stimulated the EC to support the adhesion and migration of neutrophils. Fish oil supplementation reduced the potency of monocytes from normal subjects, but not those from patients with PAD, to induce recruitment. Concurrent medication may have acted as a complicating factor. On subgroup analysis, only those free of medication showed a significant effect of fish oil. Responses before or after supplementation were not closely linked to patterns of secretion of cytokines by cultured monocytes, tested in parallel monocultures. These results suggest that fish oil can modulate the ability of monocytes to stimulate EC and that this might contribute to their protective effects against chronic inflammatory disorders. Benefits, however, may depend on existing medical status and on other treatments being received.

Quantitated transcript haplotypes (QTH) of AGTR1, reduced abundance of mRNA haplotypes containing 1166C (rs5186:A>C), and relevance to metabolic syndrome traits.

The angiotensin II type 1 receptor (AGTR1) is the main target through which angiotensin II influences cardiovascular tone, cell growth, and fluid and electrolyte balance. AGTR1 polymorphism has been reported to associate with hypertension, myocardial infarction (MI), and metabolic traits. Here we describe a novel approach to quantitation of transcript haplotypes (QTH) of AGTR1. To determine relative allelic expression from haplotypes, within-individual-between-allele ratiometric analyses in placental cDNA were developed for the transcribed SNPs rs5182:C>T (encoding p.L191) and rs5186:A>C (3'-noncoding "A1166C"). Additionally, between-individual comparisons were made using TaqMan assays applied to both homozygous and heterozygous genotypes and haplotypes. In conjunction, linkage disequilibrium (LD) and genomic haplotype associations with metabolic syndrome were examined. There was no significant difference of mRNA level for alleles of rs5182:C>T, but allele and mRNA haplotypes carrying 1166C exhibited reduced abundance. The effect was much greater in CC homozygotes than in heterozygotes. The promoter region was confirmed to be in a separate haplotype block from the AGTR1 3' region containing rs5182:C>T and rs5186:A>C. Metabolic syndrome trait associations were strongest for the 3' block generally and for the C allele of rs5186:A>C specifically. All effects were much more prominent in homozygotes, possibly reflecting interallelic interaction through feedback loops of mRNA regulation. Differential abundance of AGTR1 mRNA haplotypes may mediate clinical phenotypic observations of the AGTR1 genotype.

Role of single nucleotide polymorphisms of pro-inflammatory cytokine genes in the relationship between serum lipids and inflammatory parameters, and the lipid-lowering effect of fish oil in healthy males.

BACKGROUND AND AIMS: Lipid metabolism, obesity and inflammation are intimately related. Plasma triglycerides increase during the inflammatory response to pathogens and obesity increases inflammatory stress. Pro-inflammatory cytokines are secreted by adipocytes in uninfected obese subjects. Polymorphisms (SNPs) in cytokine genes influence the intensity of cytokine production and inflammatory stress. Fish oil has lipid-lowering and anti-inflammatory properties. The influence of cytokine gene polymorphisms on the interaction between adiposity, inflammation and the properties of fish oil is unknown. METHODS: Fasting plasma triglycerides, acute phase proteins and BMI were studied in 159 healthy men and the effect of 6 g/d fish oil for 12 weeks on the former two parameters studied. Subjects were genotyped for SNPs at positions -511, -174, +252 and -308 in the IL-1beta, IL-6, LT-alpha (TNF-beta) and TNF-alpha genes, respectively. Data were divided into three sub-groups of BMI, 16.7-22.8, 22.9-24.9 and 25.1-33.7 kg/m2, respectively. RESULTS: Correlations were apparent between CRP and triglycerides in the highest tertile r = 0.324, P < 0.05 and between CRP and serum amyloid in all tertiles. Mean concentrations of all three molecules were higher in the middle and highest tertile than in the lowest. Irrespective of BMI, CRP and triglycerides were positively correlated in subjects with a TNF-alpha-308GG, LT-alpha AG, IL-1beta-511TT and IL-6-174GG genotype. The latter three genotypes are associated with enhanced inflammation. Genotype and BMI interacted. Concentrations of triglyceride rose significantly with increasing tertile only in subjects with a LT-alpha AA genotype. CRP concentrations rose in subjects with a LT-alpha AG genotype. Triglycerides were lowered by fish oil. Pre-supplementation concentrations were correlated with the decrease, r = -0.494 P < 0.0001. Genotype influenced the effects of fish oil. A fall occurred in triglycerides, across tertiles of BMI, only in individuals possessing a LT-alpha+252 AA genotype. Irrespective of BMI, possession of an A allele of this SNP was necessary for the correlation to occur. CONCLUSIONS: Possession of genotypes associated with raised inflammatory stress strengthen the association between fasting plasma triglycerides and CRP. The ability of fish oil to exert a lipid-lowering, anti-inflammatory influence in healthy men is influenced by BMI and possession of the LT-alpha+252 A allele.