Associations have also been reported with polymorphisms of genes involved in innate or adaptive immunity. Allelic variations of tumor necrosis factor α (TNFα) and of cytotoxic T lymphocyte antigen 4 (CTLA-4), a key regulator of the adaptive immune system, have been repeatedly associated with susceptibility to different autoimmune diseases (such as type I diabetes mellitus and systemic lupus erythematosus) and were also associated with PBC [104] [105] [106] [107] [108] [109] . Although an association of CTLA-4 variants and susceptibility to PBC could not be demonstrated in all studies [110, 111] , Poupon et al. [112] most recently confirmed a potential role of TNFα and CTLA-4 variants in the pathogenesis of PBC. In 258 PBC patients and two independent control groups of 286 and 269 healthy volunteers, the authors investigated distribution of newly identified htSNPs of 15 selected candidate genes: two related to immunity encoding for CTLA-4 and TNFα, ten genes related to bile formation encoding hepatobiliary transporters, and three related to adaptive response to cholestasis encoding nuclear receptors. In a case-control analysis, only haplotype-tagging single nucleotide polymorphisms (htSNPs) in CTLA-4 and TNFα showed differences in distribution between PBC and controls, confirming their potential role in the pathogenesis of PBC. In contrast, htSNPs of the ten transporter genes as well as the three nuclear receptor genes under study were equally distributed, confirming previous studies of htSNPs in key transporters without major impact [1, 113, 114] . A strong association of the allelic variant TNFα rs 1799724 (C/T) with disease progression was shown. Most interestingly, a strong association with disease progression was also shown for AE2 rs 2303932 (T/A), a gene encoding for the apical anion exchanger 2 (AE2) in cholangiocytes and hepatocytes. In both cases, presence of the variant was associated with delayed disease progression. In a multi-variate Cox regression, the AE2 variant rs2303932 (T/A) was an independent prognostic factor for disease progression in PBC under UDCA treatment, in addition to serum bilirubin, alkaline phosphatase, and serum albumin levels which are established surrogate markers of prognosis in PBC [112] . Most recently, a landmark genetic association study was published [332] . Associations with the risk of disease were unravelled for 13 loci across the HLA class II region, two SNPs at the interleukin 12 alpha (IL12A) locus, one SNP at the interleukin 12 receptor beta 2 locus, and one previously described SNP at the CTLA4 locus. Associations with more than 10 further loci were described. Various associations with other loci have been described in individual populations, mostly of limited size. However, the vast majority have not been confirmed in independent cohorts, and to date, none of the genetic associations described in PBC have been proven sufficiently [84, 88, 108] .