Cytokine (TNF alpha, LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies.
The influence of biallelic polymorphisms in the tumour necrosis factor-alpha (TNF alpha), lymphotoxin-alpha (LT alpha) and interleukin-10 (IL-10) genes on stimulated TNF alpha 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 TNF alpha, LT alpha and IL-10 genes. Production of the TNF alpha and IL-10 was measured by ELISA in lipopolysaccharide (LPS) stimulated whole blood. Four haplotypes of the TNF alpha gene, three haplotypes of LT alpha 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-LT alpha-2 haplotype (56% vs 21%; P = 0.0007). The TNF-2 and LT alpha-2 haplotypes were associated with higher TNF alpha production in CD patients, and the TNF-4 haplotype was associated with lower TNF alpha 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 TNF alpha, LT alpha and IL-10 gene polymorphisms on cytokine production differ in CD, UC patients and controls.
Koss
K
K
Gastroenterology Unit, Radcliffe Infirmary, Oxford, UK. konradkoss@yahoo.com
Satsangi
J
J
Fanning
G C
GC
Welsh
K I
KI
Jewell
D P
DP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012907:Smoking / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10