Abstract
Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. The strongest genetic association is with HLA-DQA1*04:01, but at least three additional independent HLA haplotypes contribute to susceptibility. We used dense single nucleotide polymorphism (SNP) data in 2861 PBC cases and 8514 controls to impute classical HLA alleles and amino acid polymorphisms using state-of-the-art methodologies. We then demonstrated through stepwise regression that association in the HLA region can be largely explained by variation at five separate amino acid positions. Three-dimensional modelling of protein structures and calculation of electrostatic potentials for the implicated HLA alleles/amino acid substitutions demonstrated a correlation between the electrostatic potential of pocket P6 in HLA-DP molecules and the HLA-DPB1 alleles/amino acid substitutions conferring PBC susceptibility/protection, highlighting potential new avenues for future functional investigation.
Highlights
Primary Biliary Cholangitis (PBC; formerly known as Primary Biliary Cirrhosis) is a rare cholestatic liver disease characterized by progressive auto-immune destruction of intrahepatic bile ducts resulting in cholangitis, liver fibrosis and, eventually, cirrhosis
Previous interrogation of the UK PBC case/control data set risk [13] using classical human leukocyte antigen (HLA) alleles imputed using the package HLA IMP:01 [18, 19] had revealed four haplotypes showing independent disease associations: the well-established association at HLA-DQA1 04:01, two previously identified protective effects marked by alleles HLA-DQB1 06:02 [20] and HLA-DQB1 03:01 [1], and a novel association marked by the haplotype HLA-DRB1 04:04/HLA-DQB1 03:02
Various software packages have been developed for the imputation of classical HLA alleles using dense single nucleotide polymorphism (SNP) data; here we used the current state-of-the-art packages HLA IMP:03 [14], HLA IMP:02 [15], HIBAG [16] and SNP2HLA [17], and compared the results obtained for classical HLA alleles with those previously obtained [13] using HLA IMP:01 [18, 19]
Summary
Primary Biliary Cholangitis (PBC; formerly known as Primary Biliary Cirrhosis) is a rare cholestatic liver disease characterized by progressive auto-immune destruction of intrahepatic bile ducts resulting in cholangitis, liver fibrosis and, eventually, cirrhosis. Previous interrogation of the UK PBC case/control data set risk [13] using classical HLA alleles imputed using the package HLA IMP:01 [18, 19] had revealed four haplotypes showing independent disease associations: the well-established association at HLA-DQA1 04:01 (which forms a haplotype with HLA-DQB1 04:02 and HLADRB1 08:01), two previously identified protective effects marked by alleles HLA-DQB1 06:02 [20] and HLA-DQB1 03:01 [1], and a novel association marked by the haplotype HLA-DRB1 04:04/HLA-DQB1 03:02. Our updated analysis of the UK PBC data set, reported here, confirms these previously-observed associations, suggests potential additional independent associations, and suggests that the majority of the SNP and classical allele association in the HLA region can largely be explained by variation at five separate amino acid positions
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