DEFINING THE IMMUNOGENETIC SUSCEPTIBILITY TO PRIMARY BILIARY-CIRRHOSIS

Primary biliary cirrhosis is a chronic cholestatic disease, thought to be immune-mediated with genetic susceptibility encoded in the major h istocompatibility 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 exten ded haplotype linking HLA-DR8 and C4B2 or to both HLA-DR8 and C4B2 in dependently conferring disease susceptibility. C4B2 genotyping was per formed on 64 patients with primary biliary cirrhosis and 61 controls m atched for ethnic background and frequency of HLA-DR8. C4B2 was associ ated 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, loca ted 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 H LA-DR8-G98A-C4B2 extended haplotype. The frequency of G91A was the sam e in the disease and control populations, suggesting that G91A does no t confer disease susceptibility. These findings establish G91 as the t elomeric boundary for disease susceptibility associated with HLA-DR8, encoded on chromosome six. These studies help define the immunogenetic susceptibility locus for primary biliary cirrhosis.