The Genetic and Microbiome Core (GMC) has played a prominent role in the statistical analyses of case-control studies investigating associations of common genetic variants associated with HIV-1 risk. The GMC expertise has been utilized to determine that much of both protective and risk associations between HLA and HIV progression can be explained by the binding specificity conferred by polymorphisms at specific sites of HLA. We have also investigated the role that HLA expression plays in disease. A significant proportion of the association between HLA-C variants and HIV viral load, could be shown to be attributable to differences in expression governed by miR148A binding to certain HLA-C alleles. The GMC supported both the experimental and epidemiological work that underlie this finding. Additional uncharacterized differences give rise to a continuum of allelic lineage specific HLA-C expression levels. The work of the core was used to demonstrate that both infectious disease (HIV viral load) and autoimmunity (risk of Crohn's disease) can be associated with this continuum, treating HLA-C allelic effects as a continuous rather than a categorical variable. The GMC is quite active in the area of regulation of HLA expression. The HLA is central to immune responses and provides among the strongest epidemiological association signals in studies of both infectious and autoimmune diseases as well as for some cancers. The core participated in bioinformatic analyses of HLA-C sequences in Chinese populations, characterizing two new variants and showing that gene conversion is a rare event in the evolution of HLA-C with different regions of the gene showing congruent phylogenies. The core have also been prominent in showing that HLA-C expression (rather than binding repertoire) is an important determinant of HIV viral load and that a polymorphism of a miR148A binding site can control such expression. We were able to show that the miR binding site was originally present on all HLA-C alleles but that a rare gene conversion from HLA-B some 4 MYA generated a HLA-C allele without the binding site. The allele gave rise to half the lineages and 33% of extant HLA-C allele in a manner that independently recapitulated known functional HLA-C polymorphisms on a high expression background. Mir148A maps to chromosome 7 and is itself polymorphic, having high and low expression variants. It was possible to show that miR148A genotype influenced both autoimmune status (Crohn's disease) and infectious disease (HIV) severity in a manner indicative of action through HLA-C expression control. Since tight linkage to HLA-B generally confounds determination of HLA-C specific effects but HLA-B has no miR148A binding site, the miR148A influence are attributable to HLA-C specific disease effects. More recently the GMC has participated in the study of HLA-A expression. Our statistical expertise was used to determine the contribution of individual allelic lineages of HLA-A to expression in individuals using linear regression analysis. The role of HLA-A methylation and the effects of HLA-A expression on HIV disease risk and progression are also being investigated. HLA expression has also been implicated in transplantation outcomes and the GMC has worked with collaborators to show that expression of both HLA-C and HLA-DP can play a role in determining allograft outcomes and can be novel indicators of donor suitability. The GMC participated in analysis of the role of specific variants of the ApoL1 gene implicated in kidney disease and in trypanolysis. The GMC also participated in the study of HPV and cervical cancer in Latin American populations. Somatically mutated genes were identified using exome sequencing and the activation of the PIK3CA gene implicated in the etiology of HPV associated tumors. As part of the widening role of the GMC, facilities and personnel for microbiome preparation, sequencing and analysis have been established at the Bethesda campus. Pipelines for microbiome sequencing and downstream sequence analysis are in development and collaborations are being established. It is expected that the role of the microbiome in health will be explored and come play a larger role in GMC work for the coming year.
| Ramsuran, Veron; Hernández-Sanchez, Pedro G; O'hUigin, Colm et al. (2017) Sequence and Phylogenetic Analysis of the Untranslated Promoter Regions for HLA Class I Genes. J Immunol 198:2320-2329 |
| Lou, Hong; Villagran, Guillermo; Boland, Joseph F et al. (2015) Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway. Clin Cancer Res 21:5360-70 |
| Ramsuran, Veron; Kulkarni, Smita; O'huigin, Colm et al. (2015) Epigenetic regulation of differential HLA-A allelic expression levels. Hum Mol Genet 24:4268-75 |
| Rizvi, Syed Monem; Salam, Nasir; Geng, Jie et al. (2014) Distinct assembly profiles of HLA-B molecules. J Immunol 192:4967-76 |
| Dean, Michael; Bendfeldt, Giovana; Lou, Hong et al. (2014) Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala. Cancer Lett 351:59-63 |
| Bashirova, Arman A; Martin-Gayo, Enrique; Jones, Des C et al. (2014) LILRB2 interaction with HLA class I correlates with control of HIV-1 infection. PLoS Genet 10:e1004196 |
| Petersdorf, Effie W; Gooley, Theodore A; Malkki, Mari et al. (2014) HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation. Blood 124:3996-4003 |
| Jiménez-Morales, Silvia; Martínez-Aguilar, Nora; Gamboa-Becerra, Roberto et al. (2013) Polymorphisms in metalloproteinase-9 are associated with the risk for asthma in Mexican pediatric patients. Hum Immunol 74:998-1002 |
| McLaren, Paul J; Coulonges, Cédric; Ripke, Stephan et al. (2013) Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls. PLoS Pathog 9:e1003515 |
| Nickerson, Michael L; Im, Kate M; Misner, Kevin J et al. (2013) Somatic alterations contributing to metastasis of a castration-resistant prostate cancer. Hum Mutat 34:1231-41 |
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