At the HLA region, the variants showing the strongest associations with PBC were similar between the two data sets, with almost complete overlap of the strongest association observed between the DQB1 and find more DQA2 loci (Fig. 2B). Importantly, the association with HLA region were also confirmed and strengthened by a third GWAS, recently conducted in a very large cohort of 1840 UK PBC cases and 5163 population controls17 (Table 2). Taken together, these three GWAS identified a number of non-HLA loci, with plausible candidate genes that indicate the involvement of the innate and adaptive immune systems in the etiopathogenesis of PBC (Table 2). In particular, these findings support the role for the Toll-like

receptor, TNF, and nuclear factor kappa B (NF-κB) pathways. Among the associations consistently reported are, notably, those with the IL-12A and IL-12RB2 loci, the gene encoding the SPi-B transcription factor (SPIB), as well as two other loci, the gene click here encoding interferon regulatory factor 5 (IRF5) and the gene encoding the IKAROS family zinc finger 3 (IKZF3), and that encoding ORM1-like 2 (ORMDL3) also implicated in risk for other autoimmune diseases such as lupus and asthma, respectively. Suggestive associations were also observed between

PBC and two other loci associated with other autoimmune conditions, the signal transducer and activator of transcription 4 (STAT4) and DENND1B. Finally, the most recent UK GWAS identified novel associations between PBC and loci, such as CD80, NF-κB1, IL-7R, CXCR5, and TNFAIP217 (Table 2). These studies clearly identified PBC association with several novel non-HLA loci and added evidence of overlaps in the risk loci predisposing to PBC and other autoimmune diseases. However, all these novel genetic data allow us to make some observations. First, a greater number of studies and of subjects Alectinib nmr (cases and controls) who are studied results in a greater number of common genetic

variants associated with PBC. This suggests caution in some way and the reasonable need to redirect our future research studies, for example, to rare variants or to copy number variants or to gene expression. The second observation is the strong consistency among the findings of these three GWAS, thus suggesting the presence of a common genetic pattern for PBC. This finding is very positive, but again, caution is needed, because the first three GWAS have been performed in populations of European ancestry, and it will be important also to replicate the reported associations in non-European populations. Indeed, a recent study from Japan failed to confirm some GWAS-associated variants.84 It is currently believed the development of PBC requires that an environmental factor, particularly an infection, initiates an autoimmune reaction in a genetically predisposed individual.