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

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-DQ beta 1Leu26 (p value(Meta) = 1.24 x 10(-14)) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQ beta 1Pro55 (p value(Meta) = 8.23 x 10(-11)) located in the peptide binding region was positively associated, independently of HLA-DQ beta 1Leu26. These two amino acids are not in linkage disequilibrium (r(2) < 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-DQ beta 1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC so nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 x 10(-38)). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQ beta 1 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.

Automated summary

Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with specific amino acids in HLA-DQ beta 1. Fine-mapping the MHCII region revealed these key amino acids, explaining the allelic and SNP associations with HCV outcomes. This understanding could contribute to the design of vaccines promoting spontaneous clearance of HCV infection.