PMID- 19003916 OWN - NLM STAT- MEDLINE DCOM- 20090112 LR - 20211020 IS - 1527-3350 (Electronic) IS - 0270-9139 (Print) IS - 0270-9139 (Linking) VI - 48 IP - 6 DP - 2008 Dec TI - Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls. PG - 1906-12 LID - 10.1002/hep.22567 [doi] AB - 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. FAU - Invernizzi, Pietro AU - Invernizzi P AD - Department of Internal Medicine, Istituto Clinico Humanitas IRCCS, University of Milan, Milan, Italy. FAU - Selmi, Carlo AU - Selmi C FAU - Poli, Francesca AU - Poli F FAU - Frison, Sara AU - Frison S FAU - Floreani, Annarosa AU - Floreani A FAU - Alvaro, Domenico AU - Alvaro D FAU - Almasio, Piero AU - Almasio P FAU - Rosina, Floriano AU - Rosina F FAU - Marzioni, Marco AU - Marzioni M FAU - Fabris, Luca AU - Fabris L FAU - Muratori, Luigi AU - Muratori L FAU - Qi, Lihong AU - Qi L FAU - Seldin, Michael F AU - Seldin MF FAU - Gershwin, M Eric AU - Gershwin ME FAU - Podda, Mauro AU - Podda M CN - Italian PBC Genetic Study Group LA - eng GR - R01 DK056839/DK/NIDDK NIH HHS/United States GR - R01 DK056839-07/DK/NIDDK NIH HHS/United States GR - DK056839/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (HLA-DR Antigens) RN - 0 (HLA-DRB1 Chains) RN - 0 (HLA-DRB1*11 antigen) RN - 0 (HLA-DRB1*13 antigen) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Case-Control Studies MH - Cohort Studies MH - Female MH - Gene Frequency MH - Genetic Predisposition to Disease MH - Genotype MH - HLA-DR Antigens/*genetics MH - HLA-DRB1 Chains MH - Humans MH - Italy MH - Liver Cirrhosis, Biliary/ethnology/*genetics MH - Male MH - Middle Aged MH - Models, Genetic MH - Polymorphism, Genetic/*genetics PMC - PMC2592501 MID - NIHMS76789 FIR - Andreoletti, Marco IR - Andreoletti M FIR - Andriulli, Angelo IR - Andriulli A FIR - Baldini, Vittorio IR - Baldini V FIR - Battezzati, Pier Maria IR - Battezzati PM FIR - Benedetti, Antonio IR - Benedetti A FIR - Bernuzzi, Francesca IR - Bernuzzi F FIR - Bianchi, Francesco B IR - Bianchi FB FIR - Bianchi, Ilaria IR - Bianchi I FIR - Bignotto, Monica IR - Bignotto M FIR - Bragazzi, Maria Consiglia IR - Bragazzi MC FIR - Brunetto, Maurizia IR - Brunetto M FIR - Caimi, Marina IR - Caimi M FIR - Caliari, Lisa IR - Caliari L FIR - Caporaso, Nicola IR - Caporaso N FIR - Casella, Giovanni IR - Casella G FIR - Casiraghi, Antonietta IR - Casiraghi A FIR - Colli, Agostino IR - Colli A FIR - Colombo, Massimo IR - Colombo M FIR - Conte, Dario IR - Conte D FIR - Croce, Lory IR - Croce L FIR - Crosignani, Andrea IR - Crosignani A FIR - Dottorini, Lorenzo IR - Dottorini L FIR - Ferrari, Carlo IR - Ferrari C FIR - Fraquelli, Mirella IR - Fraquelli M FIR - Frati, Cesare E IR - Frati CE FIR - Galli, Andrea IR - Galli A FIR - Lleo, Ana IR - Lleo A FIR - Mancino, Maria Grazia IR - Mancino MG FIR - Mandelli, Giovanna IR - Mandelli G FIR - Marra, Fabio IR - Marra F FIR - Montanari, Renzo IR - Montanari R FIR - Monti, Valentina IR - Monti V FIR - Morini, Lorenzo IR - Morini L FIR - Morisco, Filomena IR - Morisco F FIR - Niro, Grazia IR - Niro G FIR - Palasciano, Giuseppe IR - Palasciano G FIR - Calmieri, Vincenzo O IR - Calmieri VO FIR - Pasini, Simone IR - Pasini S FIR - Picciotto, Antonio IR - Picciotto A FIR - Portincasa, Piero IR - Portincasa P FIR - Pozzoli, Vanila IR - Pozzoli V FIR - Spinzi, Giancarlo IR - Spinzi G FIR - Strazzabosco, Mario IR - Strazzabosco M FIR - Tiribelli, Claudio IR - Tiribelli C FIR - Toniutto, Pierluigi IR - Toniutto P FIR - Zerminai, Paola IR - Zerminai P FIR - Zuin, Massimo IR - Zuin M EDAT- 2008/11/13 09:00 MHDA- 2009/01/13 09:00 PMCR- 2009/12/01 CRDT- 2008/11/13 09:00 PHST- 2008/11/13 09:00 [pubmed] PHST- 2009/01/13 09:00 [medline] PHST- 2008/11/13 09:00 [entrez] PHST- 2009/12/01 00:00 [pmc-release] AID - 10.1002/hep.22567 [doi] PST - ppublish SO - Hepatology. 2008 Dec;48(6):1906-12. doi: 10.1002/hep.22567.