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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

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. and Cordell, Heather J. 2018. Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and primary biliary cholangitis. PLoS Genetics 14 (12) , e1007833. 10.1371/journal.pgen.1007833

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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 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Public Library of Science
ISSN: 1553-7390
Date of First Compliant Deposit: 18 December 2018
Date of Acceptance: 13 November 2018
Last Modified: 19 Dec 2018 12:15
URI: http://orca-mwe.cf.ac.uk/id/eprint/117746

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