Association of tumor necrosis factor polymorphism with primary sclerosing cholangitis

Abstract

Background/aims: Primary sclerosing cholangitis is associated with the HLA haplotypes A1-B8-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201 and DRB3*0101-DRB1*1301-DQA1*0103-DQB1* 0603. However, the interpretation of these genetic associations is controversial. One explanation may be that HLA-encoded susceptibility is due to other genes carried on these haplotypes such as the HLA class III tumor necrosis factor genes. The aim of the study was to investigate tumor necrosis factor genetics in a large series of well-defined patients.

Methods: One hundred and ten HLA genotyped patients and 126 control subjects were studied by polymerase chain reaction genotyping for 3 different tumor necrosis factor gene polymorphisms: -308, -238 and an Ncol restriction fragment length polymorphism in the lymphotoxin alpha gene.

Results: Overall, 58% of patients had the TNF2 allele, compared with 29% of controls, p(c) = 0.0001. No association was found with either of the other tumor necrosis factor polymorphisms examined. TNF2 was significantly increased in the presence of B8 and DRB3*0101 only, and was independent of DRB1*0301 (p(c)<0.04). The associations with B8 and TNF2 were stronger than the associations with any of the HLA class II alleles examined.

Conclusion: HLA-encoded genetic susceptibility to primary sclerosing cholangitis may be determined by polymorphism within the HLA class III region, in particular with the TNF2 allele.