Trans-ancestral fine-mapping of MHC reveals key amino acids associated with spontaneous clearance of hepatitis C in HLA-DQ beta 1

Accepted/In Press date: 14 December 2021

e-pub ahead of print date: 31 January 2022

Published date: 3 February 2022

Additional Information: Funding Information: Both codons we identified as associated with HCV clearance form part of a peptide-binding groove in the HLA-DQ molecule. This finding suggests that HLA-DQ binding may be critical to the net effectiveness of HCV immune responses. This inference is supported by our formal, independent HLA binding analysis. Indeed, the HLA-DQ haplotypes linked to clearance (HLA-DQA1 ∗ 03:03/HLA-DQB1 ∗ 03:01 and HLA- DQA1 ∗ 05:05/HLA- DQB1 ∗ 03:01) bound a greater number of predicted HCV peptides and showed binding with higher affinity compared to those linked to persistence (HLA-DQA1 ∗ 01:02/HLA-DQB1 ∗ 06:02 and HLA-DQA1 ∗ 05:01/HLA-DQB1 ∗ 02:01). Additionally, this finding agrees with Cramp et al. who demonstrated more robust CD4 + T cell responses in those who were HLA-DQB1 ∗ 03:01 positive, as well as a strong association with spontaneous resolution of HCV infection. 60 Likewise, Kovacs et al. demonstrated that HLA-DQB1 ∗ 03:01 was associated with increased CD8 + T cell activation. 61 Funding Information: Funding provided by National Institutes of Health R01 DA013324, AI0148049, DA033541, DA04334, R01 DA12568, U01DA036297, U01AI131314, U19AI066345, R01 HL076902, R01 DA16159, R01 DA21550, UL1 RR024996, R01HD41224, R01DA038632, R01DA026141, AI082630, DA033541, AI082630, AI066345, AI091649, and U19AI088791; AIDS Research through the Center for Inherited Diseases at Johns Hopkins University and National Institute of Allergy and Infectious Diseases. Data in this manuscript were collected by MACS and WIHS, now the MACS/WIHS Combined Cohort Study (MWCCS), which is supported by the National Institutes of Health. N.V. has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sk?odowska-Curie grant agreement No. 846520. A.S. has been funded by NIH NIAID contract Nr. 75N93019C00001. R.T.C. was supported by the MGH Research Scholars Program. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. J.C.P. has received research grant support to her institution from Gilead Sciences, Merck, and Abbvie and has served on an advisory board for Gilead Sciences and Theratechnolgies. S.H.M. have received speaker fees from Gilead Sciences not related to this work. A.H.K. serves on the Data Monitoring Committee for Kintor Pharmaceutical. Publisher Copyright: © 2022 Copyright: Copyright 2022 Elsevier B.V., All rights reserved.

Keywords: Acute Disease, Alleles, Amino Acid Substitution, Blacks, Female, Gene Expression, Genome-Wide Association Study, Genotype, HLA-DQ beta-Chains/genetics, Hepacivirus/growth & development, Hepatitis C/ethnology, Host-Pathogen Interactions/genetics, Humans, Leucine/immunology, Male, Polymorphism, Single Nucleotide, Proline/immunology, Protein Isoforms/genetics, Remission, Spontaneous, Whites

Local EPrints ID: 456833

URI: http://eprints.soton.ac.uk/id/eprint/456833

DOI: doi:10.1016/j.ajhg.2022.01.001

ISSN: 0002-9297

PURE UUID: c8a185be-018d-4237-9b89-c395534b8131

ORCID for Salim I Khakoo: orcid.org/0000-0002-4057-9091

Date deposited: 12 May 2022 16:47

Last modified: 17 Mar 2024 07:13