Genetics and Genomics of Primary Biliary Cirrhosis

Abstract

The etiological and pathogenic factors contributing to PBC development, progression, response to treatment, and ultimately, outcome remain a mystery. This lack of knowledge can be attributed to the complexity of PBC, wherein a number of environmental triggers may be culpable, but require coexisting genetic susceptibility to exert their effect. Recognition of the genomic regions harboring these heritable risk factors has been hindered by the rarity and late onset of PBC, which has rendered the collection of adequate numbers of patients and family members for genetic analyses a difficult task. Recent advancements in the discipline of genomics holds promise to fundamentally change our understanding, prevention, and therapy of PBC. This chance arises from the development of new high-throughput approaches to genotyping, providing the means to rapidly uncover many of the genetic polymorphisms that are relevant to disease. In order to move ahead, large registries and biospecimen repositories of patients with PBC, their family members, and well-matched controls need to be established, maintained, and continually expanded. At the same time, sizeable, comprehensive haplotype mapping based association studies of functionally plausible candidate gene groups (e.g. immune function genes) as well as more far reaching genome-wide association studies will be necessary to form the basis upon which the genetic predisposition to PBC can be defined. This first set of experimental data will provide the means for future fine mapping studies, resequencing efforts, functional experimentation, and elucidation of gene-environment and gene-gene interaction; perhaps paving new paths in PBC research.

CTLA4/ICOS gene variants and haplotypes are associated with rheumatoid arthritis and primary biliary cirrhosis in the Canadian population

“…In keeping with these findings, the HLA region has been identified as a key contributor to genetic risk of both RA and PBC (3,4).…”

“…Variants in the gene encoding the immunoregulatory CTLA-4 have also been implicated in both RA and PBC (3,4), but these findings have not been universally replicated, and the adjacent gene encoding another immunoregulatory protein, inducible costimulator (ICOS), has not been studied extensively. Because of the potential significance of these molecules in autoimmune disease susceptibility, we undertook an evaluation of both CTLA4 and ICOS polymorphisms as possible contributors to risk of RA or PBC in the Canadian popu- Figure 1.…”

Primary biliary cirrhosis: A 2010 update

“…CTLA4 encodes a coinhibitory immunoreceptor that is a key regulator of self-tolerance with established genetic associations to multiple autoimmune diseases and in most, but not all, genetic studies of PBC [31,33,34,[36][37][38]. Interestingly, there is an association of genetic variation at the VDR locus and susceptibility to PBC [32] thanks to the role of vitamin D not only in adaptative immunity but also in the regulation of innate immunity of the biliary tree [39].…”

“…Allelic variations in MHC class II (DR, DQ), components of the innate (C4 * Q0, C4B * 2, NRAMP1/SLC11A1, MBL, VDR) and of the adaptative (CTLA4, IL beta, TNF alpha, IL12A, IL12RB2) immune systems have been shown to be associated with the susceptibility of PBC [30][31][32][33][34]. The possible role of allelic variation of several components of the innate immune system suggests some disturbances of host resistance to microbial infection in PBC and their implication in the initiation or perpetuation of the inflammatory process.…”

Polymorphisms of genes related to endothelial cells are associated with primary biliary cirrhosis patients of Cretan origin

“…Several gene polymorphisms have been associated with the susceptibility of PBC in various populations, mainly the allelic variations in MHC class II, components of the innate [8,12,13] and of the adaptive [9,14,15] immune systems.…”