Variation within the HLA class I genes of the MHC has the greatest impact on outcome after HIV infection relative to the rest of the genome. The first HIV GWAS identified a genome-wide significant effect of rs9264942 on HIV set point viral load that was independent of all other significant hits in the region, a finding that was confirmed in subsequent studies comparing HIV controllers to noncontrollers. This variant is located 35 Kb upstream of the HLA-C locus, and is in strong linkage disequilibrium (LD) with the HLA-C coding region in people of European descent, but not in those of African ancestry. It is also associated with levels of HLA-C expression. We subsequently identified a microRNA (miRNA) binding site in the 3'untranslated region (3'UTR) of HLA-C, which is polymorphic and likely explains the differential cell surface expression of HLA-C across the various allotypes. Variation in this binding site is in near perfect linkage disequilibrium with rs9264942. We also showed that the variation in the miR binding site associates strongly with HIV viral load control. These findings are significant because prior to this, variation within the HLA-C locus was not considered to be much of a driving force in HIV restriction. Individual allelic effects of HLA-C are minimal in comparison to those at HLA-B. However, unlike HLA-B and HLA-A, HLA-C molecules are not down-regulated by HIV Nef, which allows "normal" recognition of infected cells by CTL restricted by HLA-C molecules. There still remains the question as to whether or not HLA-C expression levels have a direct influence on HIV control. If this is indeed the case, then we expect to observe the effect across ethnic groups, despite their distinct HLA-C allele frequencies and linkage disequilibrium (LD) relationships with HLA-A and -B alleles. In order to address this issue we characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in over 5000 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Further, higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. The effect of HLA-C expression level in HIV disease raises the possibility of its involvement in the risk of other human diseases. We tested this possibility in case-control cohorts of two inflammatory bowel diseases (IBD): Crohn's disease (CD) and ulcerative colitis (UC). High HLA-C expression had a deleterious effect in Crohn's disease, suggesting a broader influence of HLA expression levels in human disease. Thus, the complexity of HLA effects in disease pathogenesis go beyond peptide specificity to include the strength of immune responses as dictated by levels of HLA expression. Comparing the frequency differences between common DNA variants in disease-affected cases and in unaffected controls has been successful in uncovering the genetic component of multiple diseases. Multiple GWAS have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. We were part of a large collaborative network of cohorts and institutions involved in HIV-1 host genetic studies that sought to test for common genetic polymorphisms that influence HIV-1 acquisition. Genome-wide SNP data on over 6,300 HIV-1 infected patients of European ancestry was combined for this analysis. After imputation using the 1,000 Genomes Project reference panel, approximately 8 million common DNA variants (SNPs and indels) were tested for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 4E-11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition with the exception of CCR5delta32 homozygosity. Thus, in contrast to HIV disease control, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size. Hepatitis C virus (HCV) infection culminates in one of two distinct clinical outcomes. Approximately 60% of persons have life-long chronic infection with the associated risks for cirrhosis and hepatocellular carcinoma, whereas the remainder spontaneously eliminate infection. The most consistently replicated genetic association has been with variants near the gene for interleukin-28B (IL-28B). However, previous studies have either focused on one particular single nucleotide polymorphism (SNP) or had limited sample sizes from individual outcome groups and, thus, have restricted ability to find additional susceptibility alleles for spontaneous resolution of HCV infection. In order to address this, a GWAS was performed on 2401 persons from 13 distinct study groups for genetic associations with spontaneous resolution of HCV. Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B. On chromosome 6, allele frequency differences localized near genes for HLA class II near DQB1*03:01. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% and 15.8% of the variation in HCV resolution in persons of European and African ancestry, respectively. Nasopharyngeal carcinoma (NPC) is an epithelial malignancy that is strongly associated with EBV infection. Using GWAS and high-resolution HLA class I gene typing of study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China strong association signals involving SNPs, HLA alleles, and amino acid variants across the MHC were detected. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in the HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010791-07
Application #
8763221
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$1,007,817
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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