Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and primary biliary cholangitis

• Published in: PLoS genetics 2018-12, Vol.14 (12), p.e1007833
• Main Authors: Darlay, Rebecca, Ayers, Kristin L, Mells, George F, Hall, Lynsey S, Liu, Jimmy Z, Almarri, Mohamed A, Alexander, Graeme J, Jones, David E, Sandford, Richard N, Anderson, Carl A, Cordell, Heather J
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Sequence; Amino Acid Substitution; Amino acids; Antigens; Bile ducts; Biology and Life Sciences; Care and treatment; Cholangitis; Datasets; Development and progression; Diabetes; DQA1 protein; Electrostatic properties; Funding; Gene polymorphism; Genes; Genes, MHC Class II; Genetic aspects; Genetic Association Studies; Genetic polymorphisms; Genetic Predisposition to Disease; Genetics; Genomes; Haplotypes; Histocompatibility antigen HLA; HLA antigens; HLA Antigens - chemistry; HLA Antigens - genetics; HLA-C Antigens - genetics; HLA-DP beta-Chains - chemistry; HLA-DP beta-Chains - genetics; HLA-DQ alpha-Chains - genetics; HLA-DQ beta-Chains - genetics; HLA-DRB1 Chains - genetics; Humans; Liver Cirrhosis, Biliary - genetics; Liver Cirrhosis, Biliary - immunology; Liver diseases; Major Histocompatibility Complex; Medicine; Medicine and Health Sciences; Models, Genetic; Models, Molecular; Physical Sciences; Polymorphism, Single Nucleotide; Protein Conformation; Proteins; Regression Analysis; Research and Analysis Methods; Single-nucleotide polymorphism; Software packages; Static Electricity
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1007833

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.