Cytokine (TNFα, LTα and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies

Abstract

The influence of biallelic polymorphisms in the tumour necrosis factor-alpha (TNFα), lymphotoxin-alpha (LTα) and interleukin-10 (IL-10) genes on stimulated TNFα and IL-10 production was studied in ulcerative colitis (UC) patients, Crohn’s disease (CD) patients and in healthy controls. A polymerase chain reaction sequence-specific primer (PCR-SSP) system was developed to type nine biallelic polymorphisms, three in each of the TNFα, LTα and IL-10 genes. Production of the TNFα and IL-10 was measured by ELISA in lipopolysaccharide (LPS) stimulated whole blood. Four haplotypes of the TNFα gene, three haplotypes of LTα and three haplotypes of IL-10 were identified. No significant differences in haplotype frequencies were found between patients and controls overall. On subgroup analysis however, haplotype TNF-2 was more frequent in women with extensive colitis compared to distal colitis (31% vs 12%; P = 0.028). This difference was even greater for the combined TNF-2-LTα-2 haplotype (56% vs 21%; P = 0.0007). The TNF-2 and LTα-2 haplotypes were associated with higher TNFα production in CD patients, and the TNF-4 haplotype was associated with lower TNFα production in UC patients. The A allele in the IL-10 promoter region at position −1082 was associated with decreased IL-10 production in CD patients and controls (P = 0.005, P = 0.015 respectively). These data provide evidence that the effect of TNFα, LTα and IL-10 gene polymorphisms on cytokine production differ in CD, UC patients and controls.