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.
OBJECTIVE
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.
Markovic
Olivera
O
Institute of Human Nutrition, School of Medicine, University of Southampton, S016 7PX, UK.
O'Reilly
Gillian
G
Fussell
Helen M
HM
Turner
Stephen J
SJ
Calder
Philip C
PC
Howell
William M
WM
Grimble
Robert F
RF
D000209:Acute-Phase Proteins / Q000378:metabolism*; D000328:Adult; D000483:Alleles; D015992:Body Mass Index; D005215:Fasting; D005395:Fish Oils / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D000209:Acute-Phase Proteins; D005395:Fish Oils; D007375:Interleukin-1; D015850:Interleukin-6; D008233:Lymphotoxin-alpha; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha