Trans-ancestral fine-mapping of MHC reveals key amino acids associated with spontaneous clearance of hepatitis C in HLA-DQβ1

Ana Valencia, Candelaria Vergara, Chloe L. Thio, Nicolas Vince, Venceslas Douillard, Alba Grifoni, Andrea L. Cox, Eric O. Johnson, Alex H. Kral, James J. Goedert, Alessandra Mangia, Valeria Piazzolla, Shruti H. Mehta, Gregory D. Kirk, Arthur Y. Kim, Georg M. Lauer, Raymond T. Chung, Jennifer C. Price, Salim I. Khakoo, Laurent AlricMatthew E. Cramp, Sharyne M. Donfield, Brian R. Edlin, Michael P. Busch, Graeme Alexander, Hugo R. Rosen, Edward L. Murphy, Genevieve L. Wojcik, Mary Carrington, Pierre Antoine Gourraud, Alessandro Sette, David L. Thomas, Priya Duggal

    Research output: Contribution to journalArticle in an indexed scientific journalpeer-review

    4 Scopus citations

    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-DQB103:01, and HLA-DRB101:01. 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.

    Original languageEnglish
    Pages (from-to)299-310
    Number of pages12
    JournalAmerican Journal of Human Genetics
    Volume109
    Issue number2
    DOIs
    StatePublished - 3 Feb 2022

    Bibliographical note

    Publisher Copyright:
    © 2022

    Keywords

    • GWAS
    • HCV clearance
    • HLA imputation
    • HLA-DQβ1
    • MHC
    • fine-mapping
    • hepatitis C virus
    • host genetics
    • infection
    • trans-ancestral

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