Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis.
Genetic involvement in type 1 autoimmune hepatitis (AIH) is indicated by a marked female preponderance and strong, well-established, human leukocyte antigen (HLA) associations. These associations, however, are not universal and a number of genes outside the major histocompatibility complex may also play a role in susceptibility to type 1 AIH. Prime candidates at present are those polymorphic genes encoding the proinflammatory and immunoregulatory cytokines. The aim of this study was to investigate, for the first time, 2 members of the interleukin-1 (IL-1) family (IL-1B and IL-1RN), 3 polymorphic sites in the interleukin-10 (IL-10) gene promoter (positions -1082, -819, and -592), and 2 polymorphisms in the tumor necrosis factor-alpha (TNF-alpha) promoter (positions -308 and -238) in type 1 AIH. The study was performed on 2 independently collected DNA banks, each with appropriate controls, and throughout the analysis associations described in the first set were confirmed in the second set. Standard polymerase chain reaction (PCR)-based genotyping techniques were used. Overall there were no significant differences in the distributions of the IL-1B and IL-10 alleles, genotypes, or haplotypes in either study set. In contrast we report a significant association between type 1 AIH and TNF*2 (first set: 34% of controls vs. 49% of patients, Pc =.014 and second set: 26% vs. 56%, P =.00008). However, TNF*2 is found in strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype and stratification analysis indicates that the association with TNF*2 is interdependent with HLA DRB1*0301. This is an indication that there is more than one susceptibility allele for type 1 AIH on chromosome 6p21.3.
Cookson
S
S
Institute of Liver Studies, King's College Hospital, London, UK.
Constantini
P K
PK
Clare
M
M
Underhill
J A
JA
Bernal
W
W
Czaja
A J
AJ
Donaldson
P T
PT
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D016207:Cytokines / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D015795:HLA-B8 Antigen / Q000235:genetics; D019693:Hepatitis, Autoimmune / Q000235:genetics*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012016:Reference Values; D012795:Sialoglycoproteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016207:Cytokines; D015795:HLA-B8 Antigen; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10