title: 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.
authors.affiliation: Department of Internal Medicine, Istituto Clinico Humanitas IRCCS, University of Milan, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.forename: Carlo
authors.initials: C
authors.lastname: Selmi
authors.forename: Francesca
authors.initials: F
authors.lastname: Poli
authors.forename: Sara
authors.initials: S
authors.lastname: Frison
authors.forename: Annarosa
authors.initials: A
authors.lastname: Floreani
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Piero
authors.initials: P
authors.lastname: Almasio
authors.forename: Floriano
authors.initials: F
authors.lastname: Rosina
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.forename: Luca
authors.initials: L
authors.lastname: Fabris
authors.forename: Luigi
authors.initials: L
authors.lastname: Muratori
authors.forename: Lihong
authors.initials: L
authors.lastname: Qi
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: Mauro
authors.initials: M
authors.lastname: Podda
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D007558:Italy; D008105:Liver Cirrhosis, Biliary / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C508422:HLA-DRB1*11 antigen; C506473:HLA-DRB1*13 antigen