title: Defining the immunogenetic susceptibility to primary biliary cirrhosis.
abstract: Primary biliary cirrhosis is a chronic cholestatic disease, thought to be immune-mediated with genetic susceptibility encoded in the major histocompatibility complex. In northern Europeans, the best established associations are with HLA-DR8 and the complement allele, C4B2. These associations could be due to a single susceptibility locus on an extended haplotype linking HLA-DR8 and C4B2 or to both HLA-DR8 and C4B2 independently conferring disease susceptibility. C4B2 genotyping was performed on 64 patients with primary biliary cirrhosis and 61 controls matched for ethnic background and frequency of HLA-DR8. C4B2 was associated with HLA-DR8 (p < 0.05) in PBC. No difference in the frequency of C4B2 was detected between control and disease populations, suggesting that HLA-DR8 and C4B2 are in linkage disequilibrium and that C4B2 is not a susceptibility locus for PBC. Taq I polymorphisms were screened in the disease and control populations with the cosmid probe G91, located midway between the HLA-DR and complement loci. One G91 restriction fragment (G91A) was found to be associated with both HLA-DR8 and C4B2, at equal frequency in health and disease, providing evidence of an HLA-DR8-G91A-C4B2 extended haplotype. The frequency of G91A was the same in the disease and control populations, suggesting that G91A does not confer disease susceptibility. These findings establish G91 as the telomeric boundary for disease susceptibility associated with HLA-DR8, encoded on chromosome six. These studies help define the immunogenetic susceptibility locus for primary biliary cirrhosis.
authors.affiliation: Nuffield Department of Pathology and Bacteriology, University of Oxford, United Kingdom.
authors.forename: W Z
authors.initials: WZ
authors.lastname: Mehal
authors.forename: W L
authors.initials: WL
authors.lastname: Gregory
authors.forename: Y M
authors.initials: YM
authors.lastname: Lo
authors.forename: S J
authors.initials: SJ
authors.lastname: Cross
authors.forename: K A
authors.initials: KA
authors.lastname: Fleming
authors.forename: M F
authors.initials: MF
authors.lastname: Bassendine
authors.forename: O F
authors.initials: OF
authors.lastname: James
authors.forename: R D
authors.initials: RD
authors.lastname: Campbell
authors.forename: R W
authors.initials: RW
authors.lastname: Chapman
authors.forename: W M
authors.initials: WM
authors.lastname: Rosenberg
mesh_terms: D000483:Alleles; D001483:Base Sequence; D003165:Complement System Proteins / Q000235:genetics; D003360:Cosmids / Q000235:genetics; D004198:Disease Susceptibility / Q000276:immunology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059810:HLA-DR Serological Subtypes; D006239:Haplotypes; D006801:Humans; D007125:Immunogenetics; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000276:immunology*; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D012016:Reference Values
chemical_list: D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C041559:HLA-DR8 antigen; D015335:Molecular Probes; D003165:Complement System Proteins