Location of the 11 SNPs in the haplotype surrounding the Class II DRB1 gene on chromosome 6 (6p21.3), which had the greatest disease association of any SNP haplotype in the region (see text).

<p>The blue rectangles span the regions from the start to the stop points of the Class II genes: <i>HLA</i>-<i>DRB5</i>, <i>HLA</i>-<i>DRB1</i>, <i>HLA</i>-<i>DQA1</i>, and <i>HLA</i>-<i>DQB1</i>. The centromere of Chromosome 6 lies to the right of this portion of 6p21.3.</p

HLA type inference accuracy for HLA*PRG and two state-of-the-art algorithms.

<p>HLA type inference accuracy for HLA*PRG and two state-of-the-art algorithms.</p

Literature search flow chart.

<p>Literature search flow chart.</p

Begg’s funnel plot with pseudo 95% confidence limits for meta-analysis of rs1344706.

<p>Begg’s funnel plot with pseudo 95% confidence limits for meta-analysis of rs1344706.</p

Overview of the 1000 Genomes project samples typed for HLA genes.

<p>Ibericos from Spain (n = 14) were genotyped in the KGP but were not available for <i>HLA</i> typing at the time of the project. Chinese Han from Denver were typed for <i>HLA</i> they are currently publically available for sequencing data.</p

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-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 &lt; 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.</p