Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis

Background/aims: The incidence of primary biliary cirrhosis (PBC) is increa sed in the close relatives of patients, suggesting that genetic factors pla y a role in disease susceptibility. Decreased in vitro production of tumour necrosis factor (TNF)-alpha has been reported in PBC patients, suggesting a potential aetiological role for this cytokine. The aim of this study was to examine two biallelic polymorphisms in the promoter region of the TNF-al pha gene, which may play a role in the control of TNF-alpha secretion, as c andidate susceptibility loci in PBC. Methods: The polymorphisms at positions -238 and -308 in the TNF-alpha prom oter region were analysed by polymerase chain reaction in 168 unrelated PBC patients and 145 local unrelated, geographically matched normal individual s. All PBC subjects were also genotyped for HLA DR8, a previously identifie d susceptibility locus in PBC. Results: The -308 TNF1/TNF1 genotype was seen in a similar proportion of PB C patients (66%) and controls (60%). However, this genotype was found signi ficantly more frequently in the 95 PBC patients with more advanced disease (histological stage III/IV) (77%) than in either controls (p<0.01, OR=2.2 [ 1.2-4.0]) or the PBC patients with earlier disease (38/73 (52%), p=0.001 OR 3.1 [1.6-5.9]). Linkage between TNF -308 and HLA DR8 was not seen. No asso ciation was found between PBC and the biallelic -238 TNF-alpha polymorphism , either in the whole PBC population or the histological Stage III/IV subgr oup. Conclusions: Our study provides no evidence for involvement of the TNF-alph a -308 or -238 promoter polymorphisms in genetic predisposition to PBC. How ever. the significantly increased frequency of the -308 TNF1/TNF1 genotype seen in 95 patients with more advanced disease raises the possibility that this allele may be linked to disease progression rather than susceptibility The finding of different allele frequencies in PBC patients in different d isease subgroups emphasises the importance of clinical phenotype/case-mix i n the design of disease association studies.