From bases to basis: linking genetics to causation in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a multifactorial autoimmune disease with inherited and environmental components in pathogenesis. It is exceptional among autoimmune diseases in showing strong heritability according to familial occurrence and monozygotic twins concordance, yet with weak associations with the usual genetic risk elements for autoimmunity, such as the HLA alleles. Among the latter, there is risk (at least in some populations) conferred by HLA DRB1*08 and possibly some protection by DRB1*11. However, the inconsistency among studies on HLA is surprising, given that PBC is a relatively homogenous disease entity. Among non-HLA genes, some studies implicate polymorphisms of genes for cytotoxic T-lymphocyte antigen-4, interleukin-2, or interleukin-10; polymorphisms of the vitamin D receptor could synergize with low sunlight exposure to create deficiency of the immunoregulatory factor, activated vitamin D. A new lead is available from the finding in female subjects with PBC of an increase in the degree of monosomy of the X chromosome that is presumed to carry immune response genes. A further suggested source of inquiry is the apparent protection of African-American women from PBC. Finally, data on inheritance should be sought in PBC by descent methodology, rather than by cross-sectional association studies in cases and control subjects, and based on analysis of a large number of families with an affected member through a worldwide effort.