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

• DOI: 10.1371/journal.pgen.1007833
• Publication Date: 2018-12-03T18:30:34Z
• Authors: Rebecca Darlay; Kristin L. Ayers; George F. Mells; Lynsey S. Hall; Jimmy Z. Liu; Mohamed A. Almarri; Graeme J. Alexander; David E. Jones; Richard N. Sandford; Carl A. Anderson; Heather J. Cordell
• Keywords: Models, Molecular; Amino acid substitution; Protein Conformation; Genes, MHC Class II; Static Electricity; HLA-C Antigens; QH426-470; Polymorphism, Single Nucleotide; HLA-DQ alpha-Chains; Major Histocompatibility Complex; 03 medical and health sciences; Electrostatics; HLA Antigens; Genetics; HLA-DQ beta-Chains; Humans; Genetic Predisposition to Disease; Molecular genetics; Amino Acid Sequence; Variant genotypes; Genetic Association Studies; HLA-DP beta-Chains; 0303 health sciences; Models, Genetic; Liver Cirrhosis, Biliary; 3. Good health; Haplotypes; Amino Acid Substitution; Primary biliary cirrhosis; Haplogroups; Regression Analysis; Amino acid analysis; Research Article; HLA-DRB1 Chains

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.