79 Overall, these data indicate that these HLA class II alleles may influence the maintenance of immune tolerance as well as the penetrance of infectious agents, thus having implications in light of the proposed infectious theory in PBC etiology.1 In accordance with this, because the protective HLA alleles are associated with resistance to several infections, it can be hypothesized that the lack of such alleles might contribute to the molecular mimicry of infectious agents, leading to immune tolerance breakdown in PBC.1 The field of human genetics has rapidly changed since the recent completion of the human genome sequence, and novel, challenging

theories have been this website proposed. Decitabine Overall, thanks to dramatic advances in molecular technology linked to the field of genetics,81 we are now witnessing an explosion of new information about the allelic architecture of human complex diseases, such as PBC.82 In particular,

the ability to evaluate the entire human genome for common polymorphisms (i.e., those present in more than 5% of the general population) has allowed us to disclose more than 80 disease-susceptibility loci. The catalog of the National Cancer Institute–National Human Genome Research Institute reports an updated list of published GWAS (http://www. genome. gov/26525384). It is of great interest that the recent GWAS approaches have allowed the identification of an extended major histocompatibility complex, spanning approximately 7.6 megabases of the human genome.83 Indeed, many additional loci (most with a putative immunoregulatory role) were identified outside the well-known HLA class I, II, and III regions.83 A growing number of studies are providing evidence of genetic complexity within the MHC region in a number of disorders. In PBC, the first GWAS was recently performed in cases from Canada and the United States15 and reported significant associations with HLA, as

well as with other non-HLA loci including IL-12A, and IL-12RB2 polymorphisms. This first study manifested a sufficient statistical power by GPX6 including 536 patients with PBC and 1536 controls typed for approximately 300,000 common variants, but more solid data were soon provided by combining data sets from the Canadian–US GWAS with a separate Italian GWAS16 (Fig. 2 and Table 2). More than 610,000 common variants were examined in 457 Italian PBC cases and more than 1 million in 947 controls. When considered alone, the Italian cohort association data set achieves genome-wide significance at the HLA locus, with several other loci showing suggestive association signals (Fig. 2A,B). Analysis of the combined data set (998 cases and 8777 controls) showed many more loci to have reached the conservative genome-wide threshold P value (P < 5 × 10−8), most of these also showed P values < 5 × 10−5 in the Italian-alone cohort.