RESUMO
Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood. Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2-3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT). Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10-7) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis. Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.
RESUMO
BACKGROUND: IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. METHODS: We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. RESULTS: We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. CONCLUSIONS: The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.
Assuntos
Infecções por Citomegalovirus , Infecções por HIV , HIV-1 , Herpes Simples , Infecções Oportunistas , Sarcoma de Kaposi , Masculino , Humanos , Estudos de Coortes , Genótipo , Infecções por HIV/complicações , Infecções por HIV/genética , Herpes Simples/complicações , Herpes Simples/epidemiologia , Herpes Simples/genética , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Human immune responses to viral infections are highly variable, but the genetic factors that contribute to this variability are not well characterized. We used VirScan, a high-throughput epitope scanning technology, to analyze pan-viral antibody reactivity profiles of twins and SNP-genotyped individuals. Using these data, we determined the heritability and genomic loci associated with antibody epitope selection, response breadth, and control of Epstein-Barr virus (EBV) viral load. 107 EBV peptide reactivities were heritable and at least two Epstein-Barr nuclear antigen 2 (EBNA-2) reactivities were associated with variants in the MHC class II locus. We identified an EBV serosignature that predicted viral load in peripheral blood mononuclear cells and was associated with variants in the MHC class I locus. Our study illustrates the utility of epitope profiling to investigate the genetics of pathogen immunity, reports heritable features of the antibody response to viruses, and identifies specific HLA loci important for EBV epitope selection.
Assuntos
Anticorpos Antivirais/metabolismo , Epitopos/metabolismo , Infecções por Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Genótipo , Herpesvirus Humano 4/fisiologia , Epitopos Imunodominantes/metabolismo , Proteínas Virais/metabolismo , Adolescente , Adulto , Idoso , Estudos de Coortes , Mapeamento de Epitopos , Epitopos/genética , Infecções por Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Feminino , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Imunidade Humoral , Epitopos Imunodominantes/genética , Masculino , Pessoa de Meia-Idade , Peptídeos/genética , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Estudos Soroepidemiológicos , Carga Viral , Proteínas Virais/genética , Adulto JovemRESUMO
Background: People who inject drugs (PWID) account for some of the most explosive human immunodeficiency virus (HIV) and hepatitis C virus (HCV) epidemics globally. While individual drivers of infection are well understood, less is known about network factors, with minimal data beyond direct ties. Methods: 2512 PWID in New Delhi, India were recruited in 2017-19 using a sociometric network design. Sampling was initiated with 10 indexes who recruited named injection partners (people who they injected with in the prior month). Each recruit then recruited their named injection partners following the same process with cross-network linkages established by biometric data. Participants responded to a survey, including information on injection venues, and provided a blood sample. Factors associated with HIV/HCV infection were identified using logistic regression. Results: The median age was 26; 99% were male. Baseline HIV prevalence was 37.0% and 46.8% were actively infected with HCV (HCV RNA positive). The odds of prevalent HIV and active HCV infection decreased with each additional degree of separation from an infected alter (HIV AOR: 0.87; HCV AOR: 0.90) and increased among those who injected at a specific venue (HIV AOR: 1.50; HCV AOR: 1.69) independent of individual-level factors (p<0.001). In addition, sociometric factors, for example, network distance to an infected alter, were statistically significant predictors even when considering immediate egocentric ties. Conclusions: These data demonstrate an extremely high burden of HIV and HCV infection and a highly interconnected injection and spatial network structure. Incorporating network and spatial data into the design/implementation of interventions may help interrupt transmission while improving efficiency. Funding: National Institute on Drug Abuse and the Johns Hopkins University Center for AIDS Research.
Understanding the social and spatial relationships that connect people is a key element to stop the spread of infectious diseases. These networks are particularly relevant to combat epidemics among populations that are hard to reach with public health interventions. Network-based approaches, for example, can help to stop HIV or hepatitis C from spreading amongst populations that use injectable drugs. Yet how social and geographic connections such as acquaintances, injection partners, or preferred drug use places impact the risk of infection is still poorly mapped out. To address this question, Clipman et al. focused on people who inject drugs in New Delhi, India, a population heavily impacted by HIV and hepatitis C. Over 2500 people were recruited, each participant inviting their injection partners to also take part. The volunteers answered survey questions, including where they used drugs, and provided a blood sample to be tested. The results showed that, even after adjusting for individual risk factors, where people used drugs and with whom affected their risk of becoming infected with HIV and hepatitis C. In terms of social ties, the likelihood of HIV and hepatitis C infection decreased by about 13% for each person separating a given individual from an infected person. However, geographical networks also had a major impact. Injecting at a popular location respectively increased the odds of HIV and hepatitis C infection by 50% and 69%. In fact, even if the participant was not using drugs at these specific places, having an injection partner who did was enough to increase the risk for disease: for each person separating an individual from the location, the likelihood of being infected with HIV and hepatitis C decreased by respectively 14% and 10%. The results by Clipman et al. highlight how the relationships between physical spaces and social networks contribute to the spread of dangerous diseases amongst people who inject drugs. Ultimately, this knowledge may help to shape better public health interventions that would take into account the importance of geographical locations.
Assuntos
Coinfecção/transmissão , Infecções por HIV/transmissão , Hepatite C/transmissão , Adulto , Coinfecção/epidemiologia , Coinfecção/virologia , Estudos Transversais , Feminino , HIV/fisiologia , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Hepacivirus/fisiologia , Hepatite C/epidemiologia , Hepatite C/virologia , Humanos , Índia/epidemiologia , Masculino , Prevalência , Análise de Rede Social , Adulto JovemRESUMO
BACKGROUND: Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. METHODS: To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. RESULTS: A male-specific region near the adenosine diphosphate-ribosylation factor-like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98â ×â 10-07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR,â 1.4; P =â 2.46â ×â 10-06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. CONCLUSIONS: These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.
Assuntos
Hepatite C , Fatores Sexuais , Feminino , Estudo de Associação Genômica Ampla , Hepacivirus/genética , Hepatite C/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Proteínas Ribossômicas/genética , Septinas/genética , Carga ViralRESUMO
Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans (n = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like HLA zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines.
Assuntos
Apresentação de Antígeno/genética , Infecções por HIV , Antígenos de Histocompatibilidade Classe I , Proteínas de Membrana Transportadoras , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Proteínas do Vírus da Imunodeficiência Humana/imunologia , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/imunologia , Proteínas de Membrana Transportadoras/metabolismo , Peptídeos/imunologia , Peptídeos/metabolismo , Linfócitos T Citotóxicos/imunologia , Carga Viral/genética , Carga Viral/imunologiaRESUMO
BACKGROUND: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. METHODS: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. RESULTS: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. CONCLUSIONS: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. IMPACT: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.
Assuntos
Ácidos Graxos Ômega-6/sangue , Análise da Randomização Mendeliana/métodos , Neoplasias Pancreáticas/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Fatores de Risco , Neoplasias PancreáticasRESUMO
BACKGROUND: Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations. METHODS: Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry. RESULTS: Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 4.8%). Across the functional groups (intronic, intergenic, coding, and regulatory variants), intronic variants account for most of the estimated heritability (12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. CONCLUSIONS: Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data. IMPACT: Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.
Assuntos
Neoplasias Pancreáticas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologiaRESUMO
PURPOSE: Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data. METHODS: We analyzed Illumina Human Exome Array data for 1,488 participants of European ancestry in the Beaver Dam Eye Study who were without cataract surgery for association with nuclear sclerosis grade, controlling for age and sex. We performed single-variant regression analysis for 32,138 variants with minor allele frequency (MAF) ≥0.003. In addition, gene-based analysis of 11,844 genes containing at least two variants with MAF < 0.05 was performed using a gene-based unified burden and non-burden sequence kernel association test (SKAT-O). Additionally, both single-variant and gene-based analyses were analyzed stratified by smoking status. RESULTS: No single-variant test was statistically significant after Bonferroni correction (p < 1.6 × 10-6; top single nucleotide polymorphism (SNP): rs144458991, p = 2.83 × 10-5). Gene-based tests were suggestively associated with the gene RNF149 overall (p = 8.29 × 10-6) and among never smokers (N = 790, p = 2.67 × 10-6). CONCLUSIONS: This study did not find a significant genetic association with nuclear sclerosis, the possible association with the RNF149 gene highlights a potential candidate gene for future studies that aim to understand the genetic architecture of nuclear sclerosis.
Assuntos
Catarata/genética , DNA/genética , Exoma/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Catarata/diagnóstico , Catarata/metabolismo , Feminino , Seguimentos , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: MicroRNAs, small non-coding RNAs involved in gene regulation, are implicated in lymphomagenesis. We evaluated whether genetic variations in microRNA coding regions, binding sites, or biogenesis genes (collectively referred to as miRNA-SNPs) were associated with risk of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL), and serum levels of four lymphoma-related microRNAs. METHODS: Twenty-five miRNA-SNPs were genotyped in 180 AIDS-NHL cases and 529 HIV-infected matched controls from the Multicenter AIDS Cohort Study (MACS), and real-time polymerase chain reaction was used to quantify serum microRNA levels. Adjusted odds ratios (ORs) estimated using conditional logistic regression evaluated associations between miRNA-SNPs and AIDS-NHL risk. A semi-Bayes shrinkage approach was employed to reduce likelihood of false-positive associations. Adjusted mean ratios (MR) calculated using linear regression assessed associations between miRNA-SNPs and serum microRNA levels. RESULTS: DDX20 rs197412, a non-synonymous miRNA biogenesis gene SNP, was associated with AIDS-NHL risk (OR=1.34 per minor allele; 95% CI: 1.02-1.75), and higher miRNA-222 serum levels nearing statistical significance (MR=1.21 per minor allele; 95% CI: 0.98-1.49). MiRNA-196a2 rs11614913 was associated with decreased central nervous system (CNS) AIDS-NHL (CT vs. CC OR=0.52; 95% CI: 0.27-0.99). The minor allele of HIF1A rs2057482, which creates a miRNA-196a2 binding site, was associated with systemic AIDS-NHL risk (OR=1.73 per minor allele; 95% CI: 1.12-2.67), and decreased CNS AIDS-NHL risk (OR=0.49 per minor allele; 95% CI: 0.25-0.94). CONCLUSIONS: This study suggests that a few miRNA-SNPs are associated with AIDS-NHL risk and may modulate miRNA expression. These results support a role for miRNA in AIDS-NHL and may highlight pathways to be targeted for risk stratification or therapeutics.
Assuntos
Predisposição Genética para Doença , Linfoma Relacionado a AIDS/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
RATIONALE: The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not. OBJECTIVES: To examine genetic variants in patients with PNTM, their unaffected family members, and a control group. METHODS: Whole-exome sequencing was done on 69 white patients with PNTM and 18 of their white unaffected family members. We performed a candidate gene analysis using immune, cystic fibrosis transmembrance conductance regulator (CFTR), cilia, and connective tissue gene sets. The numbers of patients, family members, and control subjects with variants in each category were compared, as was the average number of variants per person. MEASUREMENTS AND MAIN RESULTS: A significantly higher number of patients with PNTM than the other subjects had low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue categories (35, 26, 90, and 90%, respectively). Patients with PNTM also had significantly more cilia and connective tissue variants per person than did control subjects (2.47 and 2.55 compared with 1.38 and 1.40, respectively; P = 1.4 × 10(-6) and P = 2.7 × 10(-8), respectively). Patients with PNTM had an average of 5.26 variants across all categories (1.98 in control subjects; P = 2.8 × 10(-17)), and they were more likely than control subjects to have variants in multiple categories. We observed similar results for family members without PNTM infection, with the exception of the immune category. CONCLUSIONS: Patients with PNTM have more low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue genes than their unaffected family members and control subjects. We propose that PNTM infection is a multigenic disease in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to the infection.
Assuntos
Cílios/genética , Tecido Conjuntivo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Imunidade/genética , Infecções por Mycobacterium não Tuberculosas/genética , Tuberculose Pulmonar/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Causalidade , Estudos de Coortes , Exoma , Família , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Análise de Sequência de DNARESUMO
Genome-wide association studies (GWAS) for nonsyndromic cleft lip with or without cleft palate (CL/P) have identified multiple genes as important in the etiology of this common birth defect. We performed a candidate gene/pathway analysis explicitly considering gene-gene (G × G) interaction to further explore the etiology of CL/P. Animal models have shown the WNT signaling pathway plays an important role in mid-facial development, and various genes in this pathway have been associated with nonsyndromic CL/P in previous studies. We propose a combined approach to search for possible G × G interactions using machine learning and regression-based methods to test for interactions between genes in the WNT family, and between these genes and other genes identified by GWAS in case-parent trios. Using this combined approach of regression-based and machine learning methods in CL/P case-parent trios, we found robust evidence of G × G interaction between markers in WNT5B and MAFB (empiric P-values = 0.0076 among Asian trios and P-values = 0.018 among European trios). Additional evidence for epistatic interaction between markers in WNT5A, IRF6, and C1orf107 was seen among Asian trios, and markers in the 8q24 region and WNT5B among European trios.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Fatores Reguladores de Interferon/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Wnt/metabolismo , Inteligência Artificial , Povo Asiático/genética , Epistasia Genética , Etnicidade/genética , Estudo de Associação Genômica Ampla , Humanos , Fatores Reguladores de Interferon/genética , Modelos Genéticos , Pais , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas/genética , População Branca/genética , Proteínas Wnt/genética , Proteína Wnt-5aRESUMO
MHC class I polymorphisms are known to influence outcomes in a number of infectious diseases, cancers, and inflammatory diseases. Human MHC class I H chains are encoded by the HLA-A, HLA-B, and HLA-C genes. These genes are highly polymorphic, with the HLA-B locus being the most variable. Each HLA class I protein binds to a distinct set of peptide Ags, which are presented to CD8(+) T cells. HLA-disease associations have been shown in some cases to link to the peptide-binding characteristics of individual HLA class I molecules. In this study, we show that polymorphisms at the HLA-B locus profoundly influence the assembly characteristics of HLA-B molecules and the stabilities of their peptide-deficient forms. In particular, dependence on the assembly factor tapasin is highly variable, with frequent occurrence of strongly tapasin-dependent or independent allotypes. Several polymorphic HLA-B residues located near the C-terminal end of the peptide are key determinants of tapasin-independent assembly. In vitro refolded forms of tapasin-independent allotypes assemble more readily with peptides compared to tapasin-dependent allotypes that belong to the same supertype, and, during refolding, reduced aggregation of tapasin-independent allotypes is observed. Paradoxically, in HIV-infected individuals, greater tapasin-independent HLA-B assembly confers more rapid progression to death, consistent with previous findings that some HLA-B allotypes shown to be tapasin independent are associated with rapid progression to multiple AIDS outcomes. Together, these findings demonstrate significant variations in the assembly of HLA-B molecules and indicate influences of HLA-B-folding patterns upon infectious disease outcomes.
Assuntos
Apresentação de Antígeno , Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Loci Gênicos/imunologia , Antígenos HLA-B/imunologia , Peptídeos/imunologia , Síndrome da Imunodeficiência Adquirida/genética , Síndrome da Imunodeficiência Adquirida/imunologia , Antígenos/genética , Linhagem Celular Tumoral , HIV-1/genética , HIV-1/imunologia , Antígenos HLA-B/genética , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/imunologia , Peptídeos/genética , Polimorfismo Genético/genética , Polimorfismo Genético/imunologia , Dobramento de ProteínaRESUMO
UNLABELLED: Chinese translation BACKGROUND: Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood. OBJECTIVE: To evaluate the host genetic basis for spontaneous resolution of HCV infection. DESIGN: 2-stage, genome-wide association study. SETTING: 13 international multicenter study sites. PATIENTS: 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence). MEASUREMENTS: Frequencies of 792 721 single nucleotide polymorphisms (SNPs). RESULTS: 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 and included rs12979860 (overall per-allele OR, 0.45; P = 2.17 × 10-30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall per-allele OR, 0.59; P = 1.71 × 10-16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015). LIMITATION: Epigenetic effects were not studied. CONCLUSION: IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection.
Assuntos
Cadeias beta de HLA-DQ/genética , Hepatite C/genética , Interleucinas/genética , Negro ou Afro-Americano/genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Hepatite C/virologia , Anticorpos Anti-Hepatite C , Humanos , Interferons , Masculino , Polimorfismo de Nucleotídeo Único , RNA Viral/sangue , Remissão EspontâneaRESUMO
BACKGROUND: Congenital Cytomegalovirus (CMV) infection is an important medical problem that has yet no current solution. A clinical trial of CMV glycoprotein B (gB) vaccine in young women showed promising efficacy. Improved understanding of the basis for prevention of CMV infection is essential for developing improved vaccines. RESULTS: We genotyped 142 women previously vaccinated with three doses of CMV gB for single nucleotide polymorphisms (SNPs) in TLR 1-4, 6, 7, 9, and 10, and their associated intracellular signaling genes. SNPs in the platelet-derived growth factor receptor (PDGFRA) and integrins were also selected based on their role in binding gB. Specific SNPs in TLR7 and IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon) were associated with antibody responses to gB vaccine. Homozygous carriers of the minor allele at four SNPs in TLR7 showed higher vaccination-induced antibody responses to gB compared to heterozygotes or homozygotes for the common allele. SNP rs1953090 in IKBKE was associated with changes in antibody level from second to third dose of vaccine; homozygotes for the minor allele exhibited lower antibody responses while homozygotes for the major allele showed increased responses over time. CONCLUSIONS: These data contribute to our understanding of the immunogenetic mechanisms underlying variations in the immune response to CMV vaccine.
Assuntos
Anticorpos Antivirais/biossíntese , Infecções por Citomegalovirus/prevenção & controle , Vacinas contra Citomegalovirus/imunologia , Polimorfismo de Nucleotídeo Único/imunologia , Receptores Toll-Like/imunologia , Vacinação , Adulto , Alelos , Anticorpos Antivirais/imunologia , Estudos de Coortes , Citomegalovirus/imunologia , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Vacinas contra Citomegalovirus/administração & dosagem , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Integrinas/genética , Integrinas/imunologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptores Toll-Like/genética , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologiaRESUMO
Entamoeba histolytica, a protozoan parasite, is an important cause of diarrhea and colitis in the developing world. Amebic colitis is characterized by ulceration of the intestinal mucosa. We performed microarray analysis of intestinal biopsies during acute and convalescent amebiasis in order to identify genes potentially involved in tissue injury or repair. Colonic biopsy samples were obtained from 8 patients during acute E. histolytica colitis and again 60 days after recovery. Gene expression in the biopsies was evaluated using microarray, and confirmed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). REG 1A and REG 1B were the most up-regulated of all genes in the human intestine in acute versus convalescent E. histolytica disease: as determined by microarray, the levels of induction were 7.4-fold and 10.7 fold for REG 1A and B; p=0.003 and p=0.006 respectively. Increased expression of REG 1A and REG 1B protein in the colonic crypt epithelial cells during acute amebiasis was similarly observed by immunohistochemistry. Because REG 1 protein is anti-apoptotic and pro-proliferative, and since E. histolytica induces apoptosis of the intestinal epithelium as part of its disease process, we next tested if REG 1 might be protective during amebiasis by preventing parasite-induced apoptosis. Intestinal epithelial cells from REG 1-/- mice were found to be more susceptible to spontaneous, and parasite-induced, apoptosis in vitro (p=0.03). We concluded that REG 1A and REG 1B were upregulated during amebiasis and may function to protect the intestinal epithelium from parasite-induced apoptosis.
Assuntos
Disenteria Amebiana/parasitologia , Entamebíase/parasitologia , Litostatina/genética , Adolescente , Adulto , Animais , Apoptose , Colo/parasitologia , Colo/patologia , Disenteria Amebiana/genética , Entamoeba histolytica/patogenicidade , Entamebíase/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Intestinos/parasitologia , Intestinos/patologia , Litostatina/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , RNA/genética , Adulto JovemRESUMO
Recent technological advances have allowed us to study individual genomes at a base-pair resolution and have demonstrated that the average exome harbors more than 15,000 genetic variants. However, our ability to understand the biological significance of the identified variants and to connect these observed variants with phenotypes is limited. The first step in this process is to identify genetic variation that is likely to result in changes to protein structure and function, because detailed studies, either population based or functional, for each of the identified variants are not practicable. Therefore algorithms that yield valid predictions of a variant's functional significance are needed. Over the past decade, several programs have been developed to predict the probability that an observed sequence variant will have a deleterious effect on protein function. These algorithms range from empirical programs that classify using known biochemical properties to statistical algorithms trained using a variety of data sources, including sequence conservation data, biochemical properties, and functional data. Using data from the pilot3 study of the 1000 Genomes Project available through Genetic Analysis Workshop 17, we compared the results of four programs (SIFT, PolyPhen, MAPP, and VarioWatch) used to predict the functional relevance of variants in 101 genes. Analysis was conducted without knowledge of the simulation model. Agreement between programs was modest ranging from 59.4% to 71.4% and only 3.5% of variants were classified as deleterious and 10.9% as tolerated across all four programs.
RESUMO
Human genetic variation is a determinant of recovery from acute hepatitis C virus (HCV) infection; however, to date, single-nucleotide polymorphisms (SNPs) in only a limited number of genes have been studied with respect to HCV clearance. We determined whether SNPs in 112 selected immune response genes are important for HCV clearance, by genotyping 1536 SNPs in a cohort of 343 persons with natural HCV clearance and 547 persons with HCV persistence. PLINK (version 1.05) and Haploview (version 4.1) software packages were used to perform association, permutation, and haplotype analyses stratified by African American and European American race. Of the 1536 SNPs tested, 1426 (92.8%) were successfully genotyped. In African Americans, we identified 18 SNPs located in 11 gene regions that were associated with HCV infection outcome (empirical P value, < .01). In European Americans, there were 20 SNPs located in 8 gene regions associated with HCV infection outcome. Four of the gene regions studied (TNFSF18, TANK, HAVCR1, and IL18BP) contained SNPs for which the empirical P value was <.01 in both of the race groups. In this large-scale analysis of 1426 genotyped SNPs in 112 candidate genes, we identified 4 gene regions that are likely candidates for a role in HCV clearance or persistence in both African Americans and European Americans.
Assuntos
Hepatite C/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Negro ou Afro-Americano/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos/genética , Receptor Celular 1 do Vírus da Hepatite A , Hepatite C/virologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Glicoproteínas de Membrana/genética , Receptores Virais/genética , Remissão Espontânea , Fatores de Necrose Tumoral/genética , População Branca/genéticaRESUMO
An association between tumor necrosis factor alpha (TNF-alpha) and Entamoeba histolytica diarrhea was assessed in a cohort of 138 non-related Bangladeshi children who have been prospectively followed since 2001. Peripheral blood mononuclear cells (PBMCs) obtained at study entry were purified, cultured, and stimulated with soluble amebic antigen before cytokine measurement from supernatant. Higher levels of TNF-alpha were associated with increased risk of first (P = 0.01) and recurrent E. histolytica-related diarrheal episodes (P = 0.005). Children who developed E. histolytica diarrhea had significantly higher TNF-alpha protein levels than those who experienced asymptomatic E. histolytica infection (P value = 0.027) or no infection (P value = 0.017). Microarray studies performed using RNA isolated from acute and convalescent whole blood and colon biopsy samples revealed higher but non-significant TNF-alpha messenger RNA (mRNA) levels in subjects with acute E. histolytica diarrhea compared with convalescence. We conclude that there is an association between higher TNF-alpha production and E. histolytica diarrhea.