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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, R; Ayers, KL; Mells, GF; Hall, LS; Liu, JZ; Almarri, MA; Alexander, GJ; ... Cordell, HJ; + view all (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) , Article e1007833. 10.1371/journal.pgen.1007833. Green open access

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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.

Type: Article
Title: Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and primary biliary cholangitis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1007833
Publisher version: https://doi.org/10.1371/journal.pgen.1007833
Language: English
Additional information: © 2018 Darlay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
Keywords: Amino acid analysis, Amino acid substitution, Electrostatics, Haplotypes, Molecular genetics, Primary biliary cirrhosis, Haplogroups, Variant genotypes
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
URI: https://discovery.ucl.ac.uk/id/eprint/10064001
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