Importantly, a few months later, the same protective HLA alleles were confirmed to be associated

with PBC in a large-scale case–control study from the UK.14 Because both these protective alleles are known to influence the penetrance of infectious agents, they have implications in light of the proposed infectious theory of PBC origin. However, the revived interest for HLA genes in PBC arising from these studies was soon overcome by three recent genome-wide Daporinad mouse association studies (GWAS) in PBC, which showed that the strongest associations are located in the HLA region.15-17 This review does not attempt to summarize the knowledge of the genetics of PBC, but will mainly focus on older and more recent associations with HLA

variants obtained with candidate-gene large-scale studies and GWAS, and on how these data may change the genetic landscape of PBC. CTLA-4, cytotoxic T-lymphocyte antigen-4; GWAS, genome-wide see more association studies; HLA, human leukocyte antigen; IL, interleukin; IKZF3, IKAROS family zinc finger 3; IRF5, interferon regulatory factor 5; ORMDL3, ORM1 like 2; PBC, primary biliary cirrhosis; SNP, single-nucleotide polymorphism; SPIB, SPi-B transcription factor; STAT4, signal transducer and activator of transcription 4; TNF, tumor necrosis factor. In the past, a number of reports have reported an increased risk

of developing PBC within family members of affected individuals, a scenario called “familial PBC”.18 The majority of these studies as well as population-based epidemiological reports were performed in the UK.19-22 In this geographical area, the former reported rates of PBC prevalence within family members were approximately 1%-2.4%.19, 20 Prevalence rates of familial PBC were later reported to be 6.4% in the UK22 and between 3.8% and 9.0% in a number of studies from North America, Europe, and Japan. A further estimate of the familial Teicoplanin prevalence of PBC, the sibling relative risk, was found to be 10.5% in a UK study.22 In addition, a recent large US study indicated that having a first-degree relative with PBC was significantly associated with increased risk of disease, with an odds ratio of 10.7.23 Of course, shared environmental factors by family members may well explain these findings, as suggested by data on prevalence and incidence of PBC. A role for genetics is also suggested by the frequent coexistence with other autoimmune diseases in more than one-third of patients who have PBC.23 Diseases that may coexist in patients with PBC or family members include rheumatoid arthritis, Sjögren syndrome, and autoimmune thyroid disease.