Human leukocyte antigen polymorphisms in italian primary biliary cirrhosis: A multicenter study of 664 patients and 1992 healthy controls

Abstract

Genetic factors are critical in determining susceptibility to primary biliary cirrhosis (PBC), but there has not been a clear association with human leukocyte antigen (HLA) genes. We performed a multicenter case-control study and analyzed HLA class II DRB1 associations using a large cohort of 664 well-defined cases of PBC and 1992 controls of Italian ancestry. Importantly, healthy controls were rigorously matched not only by age and sex, but 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), 3.3; 95% confidence interval (CI), 2.4-4.5] and DRB1*02 (OR 0.9; 95% CI 0.8-1.2) were significantly associated with PBC, whereas alleles DRB1*11 (OR 0.4; 95% CI 0.3-0.4) and DRB1*13 (OR 0.7; 95% CI 0.6-0.9) 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. Associated DRB1 alleles were found only in a minority of patients, whereas an additive genetic model is supported by the gene dosage effect for DRB1*11 allele and the interaction of DRB1*11,*13, and *08. Lastly, no significant associations were detected between specific DRB1 alleles and relevant clinical features represented by the presence of cirrhosis or serum autoantibodies. In conclusion, we confirm the role for HLA to determine PBC susceptibility and suggest that the effect of HLA is limited to patient subgroups. We suggest that a large whole-genome approach is required to identify further genetic elements contributing to the loss of tolerance in this disease. (HEPATOLOGY 2008;48: 1906-1912

Genetics and epigenetics in the pathogenesis of primary biliary cholangitis

“…Early investigations on associations between HLA polymorphisms and PBC were carried out >25 years ago [46]. Based on their findings, subsequent cumulative studies have provided evidence that PBC is associated with DRB1*08 as a predisposing allele and DRB1*11 and DRB1*13 as protective alleles [47,48]. Li et al conducted a meta-analysis to assess for relationships between HLA class II and disease susceptibility to PBC and demonstrated that HLA DR*07 and *08 alleles were risk factors for PBC in certain populations, while DR*11, *12, *13, and *15 alleles were protective factors [49].…”

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

“…The pathogenesis of PBC is not fully understood, but genetic factors seem to play a critical role [44]. Previous studies have shown that T cells abundantly infiltrate the hepatic tissue [45,46], and the pyruvate dehydrogenase complex might be one of the target antigens [47]. The 49AG and CT60 polymorphisms of CTLA-4 have been studied in PBC, but the results observed are controversial [48].…”

Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients

“…The etiology of PBC has yet to be conclusively elucidated, although genetic factors are considered to play a prominent role in family and population studies [2][3][4][5]. Prior reports have shown the HLA-DRB1*08 allele to be a weak and regional determinant of PBC susceptibility [6][7][8]. However, HLA alone does not explain the entire genetic predisposition to PBC, mainly since at least 80 to 90% of patients with the disease do not carry the most common HLA susceptibility alleles.…”