Primary biliary cirrhosis shows association with genetic polymorphism of tumour necrosis factor alpha promoter region

Background/Aims: Primary biliary cirrhosis is an autoimmune disease in which increased prevalence in first-degree relatives and an association with HLA DR8 suggest a genetic background. TNFα is a mediator of inflammation and immunity, and is implicated in the pathogenesis of primary biliary cirrhosis, ex vivo studies having shown reduced production of TNFα by lymphocytes from patients. Our group has previously described a biallelic promoter-region polymorphism of the TNFA gene at position -308, and demonstrated that the rare allele, TNF*2, has increased promoter function compared with the common allele, TNF*1. A further biallelic base change has been described in the TNFA gene at -238. We conducted a case-control study to assess association of these gene polymorphisms with primary biliary cirrhosis. Methods: Ninety-one patients and 213 controls were genotyped for both TNFA loci using restriction fragment length polymorphism analysis of PCR products. Results: The high production TNFA-308*2 allele was significantly under-represented among subjects with primary biliary cirrhosis (27.5% PBC, 41.6% controls, p=0.02, pc=0.04, OR for carriage of TNF*1/*1 genotype=1.89, CI=1.10-3.32). No association was shown with the TNFA -238 polymorphism. Conclusion: Primary biliary cirrhosis is associated with reduced carriage of TNF*2. This is in keeping with a protective role of TNFα against the disease.