Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS
Abstract Introduction We have reanalyzed the genomic data from the International Collaboration for the Genomics of HIV (ICGH), focusing on HIV-1 Elite Controllers (EC). Methods A genome-wide association study (GWAS) was performed, comparing 543 HIV-1 EC individuals with 3,272 uninfected controls (CT...
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2025-01-01
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| Online Access: | https://doi.org/10.1186/s12865-024-00680-6 |
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| author | Myriam Rahmouni Sigrid Le Clerc Jean-Louis Spadoni Taoufik Labib Maxime Tison Raissa Medina-Santos Armand Bensussan Ryad Tamouza Jean-François Deleuze Jean-François Zagury |
| author_facet | Myriam Rahmouni Sigrid Le Clerc Jean-Louis Spadoni Taoufik Labib Maxime Tison Raissa Medina-Santos Armand Bensussan Ryad Tamouza Jean-François Deleuze Jean-François Zagury |
| author_sort | Myriam Rahmouni |
| collection | DOAJ |
| description | Abstract Introduction We have reanalyzed the genomic data from the International Collaboration for the Genomics of HIV (ICGH), focusing on HIV-1 Elite Controllers (EC). Methods A genome-wide association study (GWAS) was performed, comparing 543 HIV-1 EC individuals with 3,272 uninfected controls (CTR) of European ancestry. 8 million single nucleotide polymorphisms (SNPs) and HLA class I and class II gene alleles were imputed to compare EC and CTR. Results Two thousand six hundred twenty-six SNPs were associated with EC (p<5.10-8), all located within the Major Histocompatibility Complex (MHC) region. Stepwise regression analysis narrowed this list to 17 SNPs. In parallel, 22 HLA class I and II alleles were associated with EC. Through meticulous mapping of the LD between all identified signals and employing reciprocal covariate analyses, we delineated a final set of 6 independent SNPs and 3 HLA class I gene alleles that accounted for most of the associations observed with EC. Our study revealed the presence of cumulative haploblock effects (SNP rs9264942 contributing to the HLA-B*57:01 effect) and that several HLA allele associations were in fact caused by SNPs in linkage disequilibrium (LD). Upon investigating SNPs in LD with the selected 6 SNPs and 3 HLA class I alleles for their impact on protein function (either damaging or differential expression), we identified several compelling mechanisms potentially explaining EC among which: a multi-action mechanism of HLA-B*57:01 involving MICA mutations and MICB differential expression overcoming the HIV-1 blockade of NK cell response, and overexpression of ZBTB12 with a possible anti-HIV-1 effect through HERV-K interference; a deleterious mutation in PPP1R18 favoring viral budding associated with rs1233396. Conclusion Our results show that MHC influence on EC likely extends beyond traditional HLA class I or class II allele associations, encompassing other MHC SNPs with various biological impacts. They point to the key role of NK cells in preventing HIV-1 infection. Our analysis shows that HLA-B*57:01 is indeed associated with partially functional MICA/MICB proteins which could also explain this marker’s involvement in other diseases such as psoriasis. More broadly, our findings suggest that within any HLA class I and II association in diseases, there may exist distinct causal SNPs within this crucial, gene-rich, and LD-rich MHC region. |
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| institution | Kabale University |
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| spelling | doaj-art-0431034ab72348adaf2ae02badabd3872025-01-12T12:14:02ZengBMCBMC Immunology1471-21722025-01-0126112210.1186/s12865-024-00680-6Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDSMyriam Rahmouni0Sigrid Le Clerc1Jean-Louis Spadoni2Taoufik Labib3Maxime Tison4Raissa Medina-Santos5Armand Bensussan6Ryad Tamouza7Jean-François Deleuze8Jean-François Zagury9Laboratoire Génomique, Bioinformatique, et Chimie Moléculaire, Conservatoire National des Arts et MétiersLaboratoire Génomique, Bioinformatique, et Chimie Moléculaire, Conservatoire National des Arts et MétiersLaboratoire Génomique, Bioinformatique, et Chimie Moléculaire, Conservatoire National des Arts et MétiersLaboratoire Génomique, Bioinformatique, et Chimie Moléculaire, Conservatoire National des Arts et MétiersLaboratoire Génomique, Bioinformatique, et Chimie Moléculaire, Conservatoire National des Arts et MétiersLaboratoire Génomique, Bioinformatique, et Chimie Moléculaire, Conservatoire National des Arts et MétiersUnité INSERM U976, Hôpital Saint-LouisLaboratoire Neuro-Psychiatrie translationnelle, Université Paris Est Créteil, INSERM U955, IMRBLaboratory for Genomics, Foundation Jean Dausset – CEPHLaboratoire Génomique, Bioinformatique, et Chimie Moléculaire, Conservatoire National des Arts et MétiersAbstract Introduction We have reanalyzed the genomic data from the International Collaboration for the Genomics of HIV (ICGH), focusing on HIV-1 Elite Controllers (EC). Methods A genome-wide association study (GWAS) was performed, comparing 543 HIV-1 EC individuals with 3,272 uninfected controls (CTR) of European ancestry. 8 million single nucleotide polymorphisms (SNPs) and HLA class I and class II gene alleles were imputed to compare EC and CTR. Results Two thousand six hundred twenty-six SNPs were associated with EC (p<5.10-8), all located within the Major Histocompatibility Complex (MHC) region. Stepwise regression analysis narrowed this list to 17 SNPs. In parallel, 22 HLA class I and II alleles were associated with EC. Through meticulous mapping of the LD between all identified signals and employing reciprocal covariate analyses, we delineated a final set of 6 independent SNPs and 3 HLA class I gene alleles that accounted for most of the associations observed with EC. Our study revealed the presence of cumulative haploblock effects (SNP rs9264942 contributing to the HLA-B*57:01 effect) and that several HLA allele associations were in fact caused by SNPs in linkage disequilibrium (LD). Upon investigating SNPs in LD with the selected 6 SNPs and 3 HLA class I alleles for their impact on protein function (either damaging or differential expression), we identified several compelling mechanisms potentially explaining EC among which: a multi-action mechanism of HLA-B*57:01 involving MICA mutations and MICB differential expression overcoming the HIV-1 blockade of NK cell response, and overexpression of ZBTB12 with a possible anti-HIV-1 effect through HERV-K interference; a deleterious mutation in PPP1R18 favoring viral budding associated with rs1233396. Conclusion Our results show that MHC influence on EC likely extends beyond traditional HLA class I or class II allele associations, encompassing other MHC SNPs with various biological impacts. They point to the key role of NK cells in preventing HIV-1 infection. Our analysis shows that HLA-B*57:01 is indeed associated with partially functional MICA/MICB proteins which could also explain this marker’s involvement in other diseases such as psoriasis. More broadly, our findings suggest that within any HLA class I and II association in diseases, there may exist distinct causal SNPs within this crucial, gene-rich, and LD-rich MHC region.https://doi.org/10.1186/s12865-024-00680-6Elite controllersHIV-1AIDSGeneticsGWASHLA |
| spellingShingle | Myriam Rahmouni Sigrid Le Clerc Jean-Louis Spadoni Taoufik Labib Maxime Tison Raissa Medina-Santos Armand Bensussan Ryad Tamouza Jean-François Deleuze Jean-François Zagury Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS BMC Immunology Elite controllers HIV-1 AIDS Genetics GWAS HLA |
| title | Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS |
| title_full | Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS |
| title_fullStr | Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS |
| title_full_unstemmed | Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS |
| title_short | Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS |
| title_sort | deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of elite control in aids |
| topic | Elite controllers HIV-1 AIDS Genetics GWAS HLA |
| url | https://doi.org/10.1186/s12865-024-00680-6 |
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