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Association of tumor necrosis factor polymorphism with primary sclerosing cholangitis
W Bernal1, M Moloney, J Underhill
1Institute of Liver Studies, King's College Hospital and King's College School of Medicine and Dentistry, London, UK.
Insights
Genetic susceptibility to primary sclerosing cholangitis may be linked to tumor necrosis factor (TNF) gene variations. The TNF2 allele was significantly more common in patients, suggesting its role in disease development.
Area of Science:
- Immunogenetics
- Gastroenterology
Background:
- Primary sclerosing cholangitis (PSC) is associated with specific HLA haplotypes.
- The role of HLA-encoded genes in PSC susceptibility is debated.
- Tumor necrosis factor (TNF) genes in the HLA class III region are potential candidates for PSC susceptibility.
Purpose of the Study:
- To investigate the association between TNF gene polymorphisms and PSC in a large patient cohort.
- To clarify the genetic basis of HLA-encoded susceptibility in PSC.
Main Methods:
- Polymerase chain reaction (PCR) genotyping was used to analyze TNF gene polymorphisms (-308, -238) and a lymphotoxin alpha gene polymorphism.
- 110 HLA-genotyped PSC patients and 126 control subjects were studied.
Main Results:
- The TNF2 allele was found in 58% of PSC patients versus 29% of controls (p=0.0001).
- No association was observed with other studied TNF polymorphisms.
- TNF2 association was strongest with HLA-B8 and DRB3*0101, independent of DRB1*0301.
Conclusions:
- Polymorphisms within the HLA class III region, specifically the TNF2 allele, may determine HLA-encoded genetic susceptibility to PSC.
- The TNF2 allele is a significant genetic factor in PSC development.
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.