Abstract
Background/aims: The incidence of primary biliary cirrhosis (PBC) is increased in the close relatives
of patients, suggesting that genetic factors play a role in disease susceptibility.
Decreased in vitro production of tumour necrosis factor (TNF)-α 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-α gene, which may play
a role in the control of TNF-α secretion, as candidate susceptibility loci in PBC.
Methods: The polymorphisms at positions −238 and −308 in the TNF-α promoter region were analysed
by polymerase chain reaction in 168 unrelated PBC patients and 145 local unrelated,
geographically matched normal individuals. All PBC subjects were also genotyped for
HLA DR8, a previously identified susceptibility locus in PBC.
Results: The −308 TNF1/TNF1 genotype was seen in a similar proportion of PBC patients (66%) and controls (60%).
However, this genotype was found significantly 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 association
was found between PBC and the biallelic −238 TNF-α polymorphism, either in the whole
PBC population or the histological Stage III/IV subgroup.
Conclusions: Our study provides no evidence for involvement of the TNF-α −308 or −238 promoter
polymorphisms in genetic predisposition to PBC. However, 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 disease subgroups emphasises
the importance of clinical phenotype/case-mix in the design of disease association
studies.
Keywords
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Article info
Publication history
Accepted:
October 1,
1998
Received in revised form:
September 21,
1998
Received:
July 31,
1998
Identification
Copyright
© 1999 Published by Elsevier Inc.
