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Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and Primary Biliary Cholangitis

Lookup NU author(s): Dr Rebecca Darlay, Dr Kristin Ayers, Dr Lynsey Hall, Professor David Jones, Professor Heather Cordell

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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 HLAalleles/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.

Publication metadata

Author(s): Darlay R, Ayers KL, Mells GF, Hall LS, Liu JZ, Almarri MA, Alexander GJ, Jones DE, Sandford RN, Anderson CA, Cordell HJ

Publication type: Article

Publication status: Published

Journal: PLOS Genetics

Year: 2018

Volume: 14

Issue: 12

Online publication date: 03/12/2018

Acceptance date: 13/11/2018

Date deposited: 13/11/2018

ISSN (electronic): 1553-7390

Publisher: Public Library of Science

URL: https://doi.org/10.1371/journal.pgen.1007833

DOI: 10.1371/journal.pgen.1007833

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