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1.
J Infect Dis ; 210(12): 1946-50, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24939907

RESUMO

Past genome-wide association studies (GWAS) involving individuals with AIDS have mainly identified associations in the HLA region. Using the latest software, we imputed 7 million single-nucleotide polymorphisms (SNPs)/indels of the 1000 Genomes Project from the GWAS-determined genotypes of individuals in the Genomics of Resistance to Immunodeficiency Virus AIDS nonprogression cohort and compared them with those of control cohorts. The strongest signals were in MICA, the gene encoding major histocompatibility class I polypeptide-related sequence A (P = 3.31 × 10(-12)), with a particular exonic deletion (P = 1.59 × 10(-8)) in full linkage disequilibrium with the reference HCP5 rs2395029 SNP. Haplotype analysis also revealed an additive effect between HLA-C, HLA-B, and MICA variants. These data suggest a role for MICA in progression and elite control of human immunodeficiency virus type 1 infection.


Assuntos
Resistência à Doença , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Adulto , Estudos de Coortes , Feminino , Estudos de Associação Genética , Infecções por HIV/virologia , Haplótipos , Humanos , Desequilíbrio de Ligação , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante , RNA não Traduzido , Adulto Jovem
2.
J Infect Dis ; 205(7): 1155-62, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22362864

RESUMO

BACKGROUND: To date, only mutations in CCR5 have been shown to confer resistance to human immunodeficiency virus type 1 (HIV-1) infection, and these explain only a small fraction of the observed variability in HIV susceptibility. METHODS: We performed a meta-analysis between 2 independent European genomewide association studies, each comparing HIV-1 seropositive cases with normal population controls known to be HIV uninfected, to identify single-nucleotide polymorphisms (SNPs) associated with the HIV-1 acquisition phenotype. SNPs exhibiting P < 10(-5) in this first stage underwent second-stage analysis in 2 independent US cohorts of European descent. RESULTS: After the first stage, a single highly significant association was revealed for the chromosome 8 rs6996198 with HIV-1 acquisition and was replicated in both second-stage cohorts. Across the 4 groups, the rs6996198-T allele was consistently associated with a significant reduced risk of HIV-1 infection, and the global meta-analysis reached genomewide significance: P(combined) = 7.76 × 10(-8). CONCLUSIONS: We provide strong evidence of association for a common variant with HIV-1 acquisition in populations of European ancestry. This protective signal against HIV-1 infection is the first identified outside the CCR5 nexus. First clues point to a potential functional role for a nearby candidate gene, CYP7B1, but this locus warrants further investigation.


Assuntos
Resistência à Doença , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Família 7 do Citocromo P450 , Europa (Continente) , Feminino , Frequência do Gene , Estudos de Associação Genética , Loci Gênicos , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Esteroide Hidroxilases/genética , Estados Unidos
3.
J Acquir Immune Defic Syndr ; 56(3): 279-84, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21107268

RESUMO

BACKGROUND: Seven genome-wide association studies (GWAS) have been published in AIDS, and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance. METHODS: We reanalyzed the data from 3 previously published GWAS, targeting specifically low-frequency SNPs (minor allele frequency <5%). Two groups composed of 365 slow progressors and 147 rapid progressors from Europe and the United States were compared with a control group of 1394 seronegative individuals using Eigenstrat corrections. RESULTS: Of the 8584 SNPs with minor allele frequency <5% in cases and controls (Bonferroni threshold = 5.8 × 10⁻6), 4 SNPs showed statistical evidence of association with the slow progressor phenotype. The best result was for HCP5 rs2395029 [P = 8.54 × 10⁻¹5, odds ratio (OR) = 3.41] in the HLA locus, in partial linkage disequilibrium with 2 additional chromosome 6 associations in C6orf48 (P = 3.03 × 10⁻¹°, OR = 2.9) and NOTCH4 (9.08 × 10⁻°7, OR = 2.32). The fourth association corresponded to rs2072255 located in RICH2 (P = 3.30 × 10⁻°6, OR = 0.43) in chromosome 17. Using HCP5 rs2395029 as a covariate, the C6orf48 and NOTCH4 signals disappeared, but the RICH2 signal still remained significant. CONCLUSIONS: Besides the already known chromosome 6 associations, the analysis of low-frequency SNPs brought up a new association in the RICH2 gene. Interestingly, RICH2 interacts with BST-2 known to be a major restriction factor for HIV-1 infection. Our study has thus identified a new candidate gene for AIDS molecular etiology and confirms the interest of singling out low-frequency SNPs to exploit GWAS data.


Assuntos
Síndrome da Imunodeficiência Adquirida/genética , Alelos , Proteínas Ativadoras de GTPase/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Adulto , Progressão da Doença , Europa (Continente) , Feminino , Sobreviventes de Longo Prazo ao HIV , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos
4.
J Infect Dis ; 202(6): 908-15, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20704485

RESUMO

BACKGROUND: The compilation of previous genomewide association studies of AIDS shows a major polymorphism in the HCP5 gene associated with both control of the viral load and long-term nonprogression (LTNP) to AIDS. METHODS: To look for genetic variants that affect LTNP without necessary control of the viral load, we reanalyzed the genomewide data of the unique LTNP Genomics of Resistance to Immunodeficiency Virus (GRIV) cohort by excluding "elite controller" patients, who were controlling the viral load at very low levels (<100 copies/mL). RESULTS: The rs2234358 polymorphism in the CXCR6 gene was the strongest signal (P=2.5 x 10(-7); odds ratio, 1.85) obtained for the genomewide association study comparing the 186 GRIV LTNPs who were not elite controllers with 697 uninfected control subjects. This association was replicated in 3 additional independent European studies, reaching genomewide significance of P(combined)=9.7 x 10(-10). This association with LTNP is independent of the CCR2-CCR5 locus and the HCP5 polymorphisms. CONCLUSIONS: The statistical significance, the replication, and the magnitude of the association demonstrate that CXCR6 is likely involved in the molecular etiology of AIDS and, in particular, in LTNP, emphasizing the power of extreme-phenotype cohorts. CXCR6 is a chemokine receptor that is known as a minor coreceptor in human immunodeficiency virus type 1 infection but could participate in disease progression through its role as a mediator of inflammation.


Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Estudos de Associação Genética , Sobreviventes de Longo Prazo ao HIV , Receptores de Quimiocinas/genética , Receptores Virais/genética , Síndrome da Imunodeficiência Adquirida/genética , Estudos de Coortes , HIV-1 , Humanos , Imunidade Inata , Masculino , Polimorfismo Genético , Receptores CXCR6 , Receptores de Quimiocinas/imunologia , Receptores Virais/imunologia
5.
J Infect Dis ; 200(8): 1194-201, 2009 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-19754311

RESUMO

BACKGROUND: Previous genomewide association studies (GWASs) of AIDS have targeted end points based on the control of viral load and disease nonprogression. The discovery of genetic factors that predispose individuals to rapid progression to AIDS should also reveal new insights into the molecular etiology of the pathology. METHODS: We undertook a case-control GWAS of a unique cohort of 85 human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced rapid disease progression, using Illumina HumanHap300 BeadChips. The case group was compared with a control group of 1352 individuals for the 291,119 autosomal single-nucleotide polymorphisms (SNPs) passing the quality control tests, using the false-discovery rate (FDR) statistical method for multitest correction. RESULTS: Novel associations with rapid progression (FDR, < or = 25%) were identified for PRMT6 (P = 6.1 x 10(-7); odds ratio [OR], 0.24), SOX5 (P = 1.8 x 10(-6); OR, 0.45), RXRG (P = 3.9 x 10(-6); OR, 3.29), and TGFBRAP1 (P = 7 x 10(-6); OR, 0.34). The haplotype analysis identified exonic and promoter SNPs potentially important for PRMT6 and TGFBRAP1 function. CONCLUSIONS: The statistical and biological relevance of these associations and their high ORs underscore the power of extreme phenotypes for GWASs, even with a modest sample size. These genetic results emphasize the role of the transforming growth factor beta pathway in the pathogenesis of HIV-1 disease. Finally, the wealth of information provided by this study should help unravel new diagnostic and therapeutic targets.


Assuntos
Síndrome da Imunodeficiência Adquirida/genética , Predisposição Genética para Doença , Genoma Humano , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Regulação da Expressão Gênica/fisiologia , Genótipo , Soropositividade para HIV , Humanos , Desequilíbrio de Ligação , Fenótipo , Polimorfismo de Nucleotídeo Único
6.
J Infect Dis ; 199(3): 419-26, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19115949

RESUMO

To elucidate the genetic factors predisposing to AIDS progression, we analyzed a unique cohort of 275 human immunodeficiency virus (HIV) type 1-seropositive nonprogressor patients in relation to a control group of 1352 seronegative individuals in a genomewide association study (GWAS). The strongest association was obtained for HCP5 rs2395029 (P=6.79x10(-10); odds ratio, 3.47) and was possibly linked to an effect of sex. Interestingly, this single-nucleotide polymorphism (SNP) was in high linkage disequilibrium with HLA-B, MICB, TNF, and several other HLA locus SNPs and haplotypes. A meta-analysis of our genomic data combined with data from the previously conducted Euro-CHAVI (Center for HIV/AIDS Vaccine Immunology) GWAS confirmed the HCP5 signal (P=3.02x10(-19)) and identified several new associations, all of them involving HLA genes: MICB, TNF, RDBP, BAT1-5, PSORS1C1, and HLA-C. Finally, stratification by HCP5 rs2395029 genotypes emphasized an independent role for ZNRD1, also in the HLA locus, and this finding was confirmed by experimental data. The present study, the first GWAS of HIV-1 nonprogressors, underscores the potential for some HLA genes to control disease progression soon after infection.


Assuntos
Síndrome da Imunodeficiência Adquirida/genética , Genoma Humano , HIV-1 , Antígenos HLA/genética , Complexo Principal de Histocompatibilidade/genética , Estudos de Coortes , Progressão da Doença , Genótipo , Soropositividade para HIV/genética , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único
7.
J Acquir Immune Defic Syndr ; 37(4): 1534-8, 2004 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-15602133

RESUMO

Three haplotypes for the CCR2-CCR5 region previously have been shown to affect AIDS progression; however, it is not known if the protective and accelerating effects of the haplotypes are relatively constant throughout infection or exert their effects early or late in HIV type 1 infection. The authors report the relative contributions to AIDS progression of CCR2 64I, CCR5 Delta32, and the CCR5 promoter haplotype +.P1.+ in the GRIV cohort, which included patients representing the extremes of the distribution for AIDS progression: rapid progressors (RP) who developed CD4 T-cell counts of <300/ mm within 3 years after the last HIV-1-seronegative test and slow progressors (SP) who were HIV-1 infected for > or =8 years with CD4 T-cell counts of >500/mm. Comparing the RP with a seroconverter control group including intermediate progressors to AIDS, we observed the early protective effect of CCR5 Delta32 (odds ratio = 0.25; P = 0.007) was similar in strength to the early susceptible effect of CCR5 +.P1.+ (odds ratio = 2.1, P = 0.01). Comparison of the intermediate control group to the SP showed weaker and less significant odd ratios, suggesting that the effect of these factors tended to be stronger on early progression; the tendency towards a disproportionately early effect was significant for CCR5 Delta32 (P = 0.04) but not for CCR5 +.P1.+ (P = 0.12). Follow-up of SP demonstrated that these polymorphisms have little effect after 8 years, because the subset of SP who had progression after study entry had the same genotype distribution as the global population of SP, suggesting that factors other than CCR5 or CCR2 genetic variants must be responsible for the long-term maintenance of nonprogression.


Assuntos
Síndrome da Imunodeficiência Adquirida/genética , Infecções por HIV/genética , HIV-1 , Haplótipos/fisiologia , Receptores CCR5/genética , Receptores de Quimiocinas/genética , Estudos de Coortes , Progressão da Doença , Seguimentos , Humanos , Receptores CCR2 , População Branca
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