title: Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis.
abstract: Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with human leukocyte antigen (HLA)-region polymorphisms. To determine if associations can be explained by classical HLA determinants, we studied Italian, 676 cases and 1440 controls, genotyped with dense single-nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (P=1.59 × 10(-11)) was the strongest predisposing allele, whereas DRB1*11 (P=1.42 × 10(-10)) was protective. Additionally, DRB1*14 and the DPB1 association (DPB1*03:01; P=9.18 × 10(-7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC.
authors.affiliation: Department of Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: P
authors.initials: P
authors.lastname: Invernizzi
authors.forename: M
authors.initials: M
authors.lastname: Ransom
authors.forename: S
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: R
authors.initials: R
authors.lastname: Kosoy
authors.forename: A
authors.initials: A
authors.lastname: Lleo
authors.forename: R
authors.initials: R
authors.lastname: Shigeta
authors.forename: A
authors.initials: A
authors.lastname: Franke
authors.forename: F
authors.initials: F
authors.lastname: Bossa
authors.forename: C I
authors.initials: CI
authors.lastname: Amos
authors.forename: P K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: K A
authors.initials: KA
authors.lastname: Siminovitch
authors.forename: D
authors.initials: D
authors.lastname: Cusi
authors.forename: P I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: M
authors.initials: M
authors.lastname: Podda
authors.forename: M E
authors.initials: ME
authors.lastname: Gershwin
authors.forename: M F
authors.initials: MF
authors.lastname: Seldin
mesh_terms: D016022:Case-Control Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059868:HLA-DP beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D007558:Italy; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D059811:HLA-DRB1 Chains