Gastroenterology

Gastroenterology

Volume 127, Issue 2, August 2004, Pages 485-492
Gastroenterology

Clinical-liver, pancreas, and biliary tract
Primary biliary cirrhosis in monozygotic and dizygotic twins: Genetics, epigenetics, and environment

https://doi.org/10.1053/j.gastro.2004.05.005Get rights and content

Abstract

Background & Aims: There is growing evidence that the interplay of genetic susceptibility and environmental factors leads to primary biliary cirrhosis (PBC). In particular, family members of an infected individual have up to a 100-fold higher risk of developing PBC. Although concordant rates for identical twins in other autoimmune diseases range between 25% and 50%, there are no such data on PBC. Accordingly, we evaluated the concordance of PBC in a genetically defined population of twin sets and evaluated the clinical characteristics between concordant subjects. Methods: We identified 16 pairs of twins within a 1400-family cohort followed up by several centers worldwide, evaluated the diagnosis of PBC in all individuals, and determined the zygosity of sets reported as identical by the analysis of 2 highly variable HLA class II regions and 5 short tandem repeats. Results: Eight of 16 sets of twins were monozygotic. In 5 of 8 monozygotic twin sets, both individuals had PBC (pairwise concordance rate, 0.63). Among the dizygotic twins (n = 8), no set was found to be concordant for PBC. Interestingly, the age at onset of disease was similar in 4 of 5 concordant sets of monozygotic pairs; however, there were differences in natural history and disease severity. Conclusions: The concordance rate of PBC in identical twins is among the highest reported in autoimmunity. However, discordant pairs were identified. The data show not only the role of genetics but also emphasize that either epigenetic factors and/or environment play a critical role.

Section snippets

Subjects

As part of a long-term effort, our laboratory has collaborated with tertiary referral centers as well as the PBCers, an Internet group of patients. This database includes information on the presence of twins within families that have at least one index case of PBC. At the time this study was initiated, we estimate that there were approximately 1400 families in the database; within this group, we requested information as to whether any sets of twins were present. The investigators involved

Diagnosis of PBC and determination of zygosity

Based on internationally accepted criteria,1, 9 we confirmed the diagnosis in 21 of 21 patients previously diagnosed with PBC by their referring physicians. In the remaining 11 of 11 individuals, we confirmed the absence of PBC, once again as noted by their referring physicians. No doubtful diagnosis of PBC (i.e., only one criterion fulfilled) was encountered. Results obtained by genetic analysis (combining HLA and STR independent typings) confirmed the monozygosity of the 8 twin pairs referred

Discussion

A large number of genetic and epidemiologic studies in PBC suggest a variable prevalence of disease in different geographic areas as well as a significant risk for development of disease in first-degree relatives of an affected subject.2, 3, 13 In addition, the relatives of affected diseased individuals often develop PBC within a short time of the first case, suggesting environmental influences.13 A large number of discrete genetic alleles have been studied in PBC, but there has not been

Acknowledgements

The authors thank Joseph Schauer (Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA) for STRs typing and Drs. Peter Stastny and Robert Vorhaben (Histocompatibility Laboratory, Transplant Immunology Section, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX) for HLA typing.

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    Supported by National Institutes of Health grant 39588.

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