69 Among populations of Asian ethnicity, studies from Japan failed to find a consistent picture of HLA class II associations with PBC,50, 51, 60 with an

association between PBC and DR2 in one,50 DPB1*0501 in another,60 and DRB1*0803 in a third.51 However, although there was a lack of consistent associations between specific DRB1 alleles and PBC in Japan, a recent study suggested that different HLA variants may relate to clinical features of disease. Indeed, Nakamura and colleagues reported a strong association of an HLA-DRB1*0405 and DRB1*0803 with disease only in the subset of patients positive for anti-sp100 (odds ratio = 1.61), a well-known PBC-specific LY2606368 serum anti-nuclear autoantibody, and anticentromere antibodies (odds ratio = 2.30).70 Interestingly, Hirschfield et al. found similar data in Caucasian populations.73

Also, because of the potential clinical implication, future association studies should address the link between different HLA variants and immunological phenotypes in PBC. Overall, we can conclude that the picture of HLA class II involvement in PBC was quite complex AZD0530 and uninteresting until recently. On the basis of the above data, it is clear why until recently HLA variants did not arouse great interest of basic and clinical researchers working to characterize the molecular mechanisms that contribute to disease development, and more specifically, for understanding the role of genetics in PBC. This began to change when our group showed that beyond the consistent (but weak) positive

association with HLA DRB1*08 allele, PBC was also strongly associated with two protective HLA variants, DRB1*11 and DRB1*13 (first reported in abstract form in 200512).13 In particular, by typing for HLA class II polymorphisms in a large cohort of 664 Italian patients with PBC and 1992 controls, we confirmed the known positive association medchemexpress with DRB1*08 (odds ratio = 3.3), whereas we reported for the first time the protective alleles DRB1*11 (odds ratio = 0.4) and DRB1*13 (odds ratio = 0.7). A weak association with HLA DRB1*02 was also found, and only the associations with DRB1*08 and DRB1*11 were common to all geographical areas of Italy (Northern, Central, and Southern Italy).13 These results were later confirmed in a large UK set of patients and controls in which protection against PBC was associated with DRB1*13 (odds ratio = 0.65) along with a positive association with the class II MHC allele DRB1*0801 (odds ratio = 3.05).14 The finding is of great interest, because the two HLA variants found to be protective for PBC suggest possible disease mechanisms as having a protective role for multiple infectious diseases. Indeed, these studies suggest that the HLA-DRB1*11 allele exerts a strong protective role against hepatitis C virus,74 human papilloma viruses,75 and human immunodeficiency virus.