@article{adf12fda8999439c948c4bd6fad884d9,
title = "Trans-ancestral fine-mapping of MHC reveals key amino acids associated with spontaneous clearance of hepatitis C in HLA-DQβ1",
abstract = "Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQβ1Leu26 (p valueMeta = 1.24 × 10−14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQβ1Pro55 (p valueMeta = 8.23 × 10−11) located in the peptide binding region was positively associated, independently of HLA-DQβ1Leu26. These two amino acids are not in linkage disequilibrium (r2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1∗03:01, and HLA-DRB1∗01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQβ1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10−38). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQβ1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection.",
keywords = "GWAS, HCV clearance, HLA imputation, HLA-DQβ1, MHC, fine-mapping, hepatitis C virus, host genetics, infection, trans-ancestral",
author = "Ana Valencia and Candelaria Vergara and Thio, {Chloe L.} and Nicolas Vince and Venceslas Douillard and Alba Grifoni and Cox, {Andrea L.} and Johnson, {Eric O.} and Kral, {Alex H.} and Goedert, {James J.} and Alessandra Mangia and Valeria Piazzolla and Mehta, {Shruti H.} and Kirk, {Gregory D.} and Kim, {Arthur Y.} and Lauer, {Georg M.} and Chung, {Raymond T.} and Price, {Jennifer C.} and Khakoo, {Salim I.} and Laurent Alric and Cramp, {Matthew E.} and Donfield, {Sharyne M.} and Edlin, {Brian R.} and Busch, {Michael P.} and Graeme Alexander and Rosen, {Hugo R.} and Murphy, {Edward L.} and Wojcik, {Genevieve L.} and Mary Carrington and Gourraud, {Pierre Antoine} and Alessandro Sette and Thomas, {David L.} and Priya Duggal",
note = "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: {\textcopyright} 2022",
year = "2022",
month = feb,
day = "3",
doi = "10.1016/j.ajhg.2022.01.001",
language = "English (US)",
volume = "109",
pages = "299--310",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",
}