The genetic epidemiological characterization of variants associated with HIV control was investigated using a variety of statistical approaches. The Genetic Core was responsible for part of the statistical analysis in a case-control study which, apart from CCR5 polymorphism, revealed little or no association of common genetic variants associated with HIV-1 acquisition. The Genetic Core statistical expertise was utilized in another large study, which determined 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. The study of individual gene effects was also supported by the core epidemiological expertise. Much 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 Genetic Core 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. Both tapasin-dependent and independent folding is used by different HLA-B allotypes and the core could help show that the independent pathways associate with more rapid progression to multiple AIDS outcomes using statistical epidemiology. HLA class II genes appear less prominent in control of HIV. Nevertheless, DRB1*13:03 could be shown to associate with lower viral load in two independent populations. Furthermore DRB1 genes could be shown to exert effects on viral load through control of HIV replication mediated through peptide presentation primarily involving HIV Gag and Nef products. The Genetic Core was also involved in showing that polymorphisms of myelomonocytic cell HLA receptors (specifically LILRB2) have a role in the determination of HIV viral load through the strength of their interaction with HLA-B. The Genetic Core is quite active in the area of regulation of HLA-C 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. Staff of the Genetic Core played the leading role in characterizing a fusion transcript of MSMB (exons 1-2) with NCOA4 (exons 2-10). The fusion transcript is associated with MSMB promoter variants involved in increased risk of prostate cancer. Five metastatic castration-resistant prostate tumors as well as healthy tissue were exome sequenced to enabled comparison of shared and unique somatic mutations between tumors. The sequencing of the mutant genes in other metastatic tumors, allowed inference of the chronology of mutations. The core was particularly involved in characterizing the TET2 missense mutations. The heterogeneity in worldwide incidence of prostate cancer is considered as evidence of undiscovered risk factors. Exome and whole genome sequencing are argued to be methods by which the indeterminate risk factors may be identified (14). The core was involved in the characterization by sequence analysis of retinoblastomas in pediatric patients from Guatemala. Five of nine mutations described were novel and the core was responsible for sample preparation and for characterizing the hypermethylation of RB1 that was found to associate with development of the retinablastomas. A transmission disequilibrium test was used to identify risk alleles of KIR and HLA in familial trios of women with cervical cancer or neoplasia. Certain HLA-C alleles that act as ligands for KIR were found to increase risk, particularly for HPV16 or HPV18 subtype infections. The core undertook the statistical analysis for these findings. Three SNPs in the MMP-9 gene were found to associate with childhood athsma in a case-control study in a Mexican population. Two of the SNP had Odds-ratios 2.0 and one was found to associate with higher athsma risk in females. The Genetic Core was responsible for the sample preparation and SNP characterization. A novel variant of HLA-DPB1 3'UTR was found to significantly associate with HBV recovery in two populations. Analysis by the core demonstrated that the SNP distinguished high and low risk alleles and that risk itself is associated with higher allelic expression levels of DPB1. Mutations in the ATP-binding cassette transporter gene, ABCC6, cause Pseudoxanthoma elasticum (PXE) and premature atherosclerosis in humans. The zebrafish abcc6 genes was used to model knockdown using morpholinos. Knockdown of the abcc6a gene was found to be embryonic lethal, but could be rescued using a mouse ABCC6 transcript.
| 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 |
| Dean, Michael; Lou, Hong (2013) Genetics and genomics of prostate cancer. Asian J Androl 15:309-13 |
| Ranasinghe, Srinika; Cutler, Sam; Davis, Isaiah et al. (2013) Association of HLA-DRB1-restricted CD4? T cell responses with HIV immune control. Nat Med 19:930-3 |
| 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 |
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