LE BASI GENETICHE DELLA CIRROSI BILIARE PRIMITIVA: DAGLI STUDI DI ASSOCIAZIONE SU SINGOLO GENE AGLI STUDI SULL'INTERO GENOMA

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology. Genetic factors are critical in determining susceptibility to PBC, but there has not been a clear association with specific genes. A multicenter case-control study was performed and HLA class II DRB1 associations were analyzed using a large cohort of 664 cases of PBC and 1,992 controls of Italian ancestry; healthy controls were rigorously matched by age, sex, and also for the geographical origin of the proband four grandparents (Northern, Central, and Southern Italy). After correction for multiple testing, DRB1*08 [odds ratio (OR) 3.35] and DRB1*02 (OR 0.9) were significantly associated with PBC, whereas alleles DRB1*11 (OR 0.4) and DRB1*13 (OR 0.7) were protective. When subjects were stratified according to their grandparental geographical origin, only the associations with DRB1*08 and DRB1*11 were common to all three areas. No significant associations were detected between specific DRB1 alleles and relevant clinical features represented by the presence of cirrhosis or serum autoantibodies. To further define the genetic factors conferring risk for PBC a genome-wide association screen for PBC was performed in an Italian cohort of 453 patients and 945 controls. In particular, 610,000 and 1 milion common variants were evaluated in PBC cases and controls, respectively. The results confirmed also by genome-wide approach a significant association at the HLA region. In addition a combined meta-analysis using a Canadian dataset showed a strong IL12A and IL12RB associations and identified newly associated loci at SPIB (OR 1.46), IRF5-TNPO3 (OR 1.63) and 17q12-21 (OR 1.38)