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Valli De Re Laura Caggiari Mariangela De Zorzi Ombretta Repetto Anna Linda Zignego Francesco Izzo Maria Lina Tornesello Franco Maria Buonaguro Alessandra Mangia Domenico Sansonno Vito Racanelli Salvatore De Vita Pietro Pioltelli Emanuela Vaccher Massimiliano Beretta Cesare Mazzaro Massimo Libra Andrea Gini Antonella Zucchetto Renato Cannizzaro Paolo De Paoli 《PloS one》2015,10(2)
BackgroundThe variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression.ConclusionsOur data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-α therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases. 相似文献
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Valli De Re Laura Caggiari Mariangela De Zorzi Renato Talamini Vito Racanelli Mario D’ Andrea Angela Buonadonna Vittorina Zagonel Erika Cecchin Federico Innocenti Giuseppe Toffoli 《PloS one》2014,9(1)
Objective
To explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI).Methods
A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progression (TTP) and overall survival (OS) were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.Results
For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1). After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no association with KIR/HLA genes was observed.Conclusion
This study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation. 相似文献4.
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Luciana de Brito Vargas Marcia H Beltrame Brenda Ho Wesley M Marin Ravi Dandekar Gonzalo Montero-Martín Marcelo A Fernndez-Via A Magdalena Hurtado Kim R Hill Luiza T Tsuneto Mara H Hutz Francisco M Salzano Maria Luiza Petzl-Erler Jill A Hollenbach Danillo G Augusto 《Molecular biology and evolution》2022,39(1)
The killer-cell immunoglobulin-like receptors (KIR) recognize human leukocyte antigen (HLA) molecules to regulate the cytotoxic and inflammatory responses of natural killer cells. KIR genes are encoded by a rapidly evolving gene family on chromosome 19 and present an unusual variation of presence and absence of genes and high allelic diversity. Although many studies have associated KIR polymorphism with susceptibility to several diseases over the last decades, the high-resolution allele-level haplotypes have only recently started to be described in populations. Here, we use a highly innovative custom next-generation sequencing method that provides a state-of-art characterization of KIR and HLA diversity in 706 individuals from eight unique South American populations: five Amerindian populations from Brazil (three Guarani and two Kaingang); one Amerindian population from Paraguay (Aché); and two urban populations from Southern Brazil (European and Japanese descendants from Curitiba). For the first time, we describe complete high-resolution KIR haplotypes in South American populations, exploring copy number, linkage disequilibrium, and KIR–HLA interactions. We show that all Amerindians analyzed to date exhibit the lowest numbers of KIR–HLA interactions among all described worldwide populations, and that 83–97% of their KIR–HLA interactions rely on a few HLA-C molecules. Using multiple approaches, we found signatures of strong purifying selection on the KIR centromeric region, which codes for the strongest NK cell educator receptors, possibly driven by the limited HLA diversity in these populations. Our study expands the current knowledge of KIR genetic diversity in populations to understand KIR–HLA coevolution and its impact on human health and survival. 相似文献
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BackgroundInterferon gamma (IFN-γ) is a key regulatory cytokine, which plays an important role in antiviral defense of an infected host. However, the association between the IFN-γ +874T/A gene polymorphism and hepatitis virus-related diseases is heterogeneous.MethodsBased on the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, a comprehensive literature search of eligible studies in Embase, Pubmed, and the Cochrane Library was undertaken through November 2014. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were used to measure the strength of the models.ResultsSeventeen case-control articles, including 24 studies with 5503 individuals, met the inclusion criteria. The results indicated a statistically significant association between the IFN-γ +874T/A polymorphism and hepatitis virus—related diseases in a recessive gene model (AA vs. TT+TA: OR=1.350, 95% CI=1.101-1.657, P=0.004, I2%=54.3, and PQ=0.001 for heterogeneity), especially in Asians (OR=1.407, 95% CI=1.035-1.911, P=0.029, I2%=61.9, and PQ=0.005 for heterogeneity) and hepatitis B virus (HBV)–related disease (OR=1.486, 95% CI=1.195–1.849, P=0.000, I2%=40.4, and PQ=0.053 for heterogeneity).ConclusionsThe evidence suggests that the IFN-γ +874T/A polymorphism increases the risk of hepatitis virus—related diseases, especially in Asians and HBV—related diseases. Further studies on this topic in different ethnicities, especially genome-wide association studies, should be conducted to strengthen our results. 相似文献
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Qi Y Martin MP Gao X Jacobson L Goedert JJ Buchbinder S Kirk GD O'Brien SJ Trowsdale J Carrington M 《PLoS pathogens》2006,2(8):e79
The compound genotype KIR3DS1/HLA-B Bw4-80I, which presumably favors natural killer cell activation, has been implicated in protection against HIV disease. We show that this genotype confers dual protection over the course of HIV disease; early direct containment of HIV viral load, and late specific defense against opportunistic infections, but not AIDS-related malignancies. The double protection of KIR3DS1/Bw4-80I in an etiologically complex disease such as AIDS, along with the disease specificity of its effects is conceptually novel and underscores the intricacy of host immunogenetics against HIV/AIDS. 相似文献
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Luz María Medrano Bárbara Dema Arturo López-Larios Carlos Maluenda Andrés Bodas Natalia López-Palacios M. ángeles Figueredo Miguel Fernández-Arquero Concepción Nú?ez 《PloS one》2012,7(10)
Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB1*03∶01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB1*03∶01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH) 8.1, AH 18.2 or non-conserved haplotype) after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB1*03∶01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03∶01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals. 相似文献
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BackgroundWe analyzed whether difference exist in the clinical manifestations and outcomes of hepatocellular carcinoma (HCC) according to the two major etiologies of HCC from a nationwide, population-based, random HCC registry.MethodsOf the 31,521 new HCC cases registered at the Korea Central Cancer Registry between 2003 and 2005, 4,630 (14.7%) were randomly abstracted, and followed up until December 2011. Of those, 2,785 hepatitis B virus (HBV)-related and 447 hepatitis C virus (HCV)-related HCC patients were compared.ResultsThe mean annual incidence rates of HBV- and HCV-related HCC incidence per 100,000 persons were 20.8 and 4.9, respectively. The annual incidence rate of HBV-related HCC peaked at 50–59 age group (46.5 per 100,000 persons), while the annual incidence rate of HCV-related HCC increased gradually to the ≥70 year age group (13.2 per 100,000 persons). Large tumors (≥5 cm) and portal vein invasion at initial diagnosis were more frequent in HBV-related HCC, while multiple tumors were more frequent in HCV-related HCC. In outcome analysis, HBV-related HCC showed poorer survival than HCV-related HCC [median survival: 1.34 vs. 2.17 years, adjusted hazard ratio (95% confidence interval): 0.88 (0.78–0.98), P = 0.03, adjusted for age, gender, Child-Pugh class, AJCC/mUICC stage, and initial treatment modality]. However, when divided according to the AJCC/mUICC stage, survival difference was observed only for those with AJCC/mUICC stage IV tumor, but not for AJCC/mUICC stage I, II or III tumors. The treatment outcome of each modality (resection, ablation, and transartherial chemoeombolization) was comparable between the two etiologies.ConclusionHBV-related and HCV-related HCC have clear differences in clinical manifestation, requiring different screening strategy according to etiology to optimize HCC surveillance in HBV-endemic area. However, etiology did not affect treatment outcomes and long-term survival within the same stage except for far advanced tumors. 相似文献
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Interactions between Drosophila C virus (DCV) and its natural host, Drosophila melanogaster, were investigated using 15 geographical population samples infected by intraabdominal inoculation. These strains derived from natural populations of D. melanogaster differed in susceptibility to the DCV(C). One strain was ``partially tolerant'. Isofemale lines obtained from one susceptible and one partially tolerant strain were studied. The partially tolerant phenotype was dominant, and there was no difference between F(1) progeny of direct and reciprocal crosses. Analysis of F(2) progeny showed that neither sex-linked genes nor maternal effects are involved in susceptibility to DCV(C). The partially tolerant strain phenotype was dominant and segregated with chromosome III. Two nonexclusive hypotheses are proposed to explain chromosome III gene action. 相似文献
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Genetic Diversity and Tissue Compartmentalization of the Hepatitis C Virus Genome in Blood Mononuclear Cells, Liver, and Serum from Chronic Hepatitis C Patients 总被引:4,自引:2,他引:2
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Sonia Navas Julio Martín Juan Antonio Quiroga Inmaculada Castillo Vicente Carreo 《Journal of virology》1998,72(2):1640-1646
The degree of genetic variability in the hypervariable region 1 of hepatitis C virus (HCV) was analyzed by cloning and sequencing HCV genomes obtained in paired samples of serum, liver tissue, and peripheral blood mononuclear cells (PBMC) from four chronic hepatitis C patients. Genetic variability in serum was higher than in liver tissue or PBMC at the level of complexity (the number of different sequences obtained from each type of tissue) as well as at the level of genetic distance between all pairs of sequences within each tissue (compared by the Student t test; P < 0.001 for two patients and P < 0.01 for another). The spectrum of viral genomes differed among the three types of tissue, as shown by segregation of sequences according to their tissue of origin in phylogenetic analysis and by statistical analysis of mean genetic distances observed between sequences obtained from different tissues (P < 0.001), but sequences from liver tissue and PBMC were more closely related to each other than to those from serum. 相似文献
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Yuichi Nozawa Takeji Umemura Satoru Joshita Yoshihiko Katsuyama Soichiro Shibata Takefumi Kimura Susumu Morita Michiharu Komatsu Akihiro Matsumoto Eiji Tanaka Masao Ota 《PloS one》2013,8(12)
Natural killer cell responses play a crucial role in virus clearance by the innate immune system. Although the killer immunoglobulin-like receptor (KIR) in combination with its cognate human leukocyte antigen (HLA) ligand, especially KIR2DL3-HLA-C1, is associated with both treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection in Caucasians, these innate immunity genes have not been fully clarified in Japanese patients. We therefore investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of interleukin (IL) 28B (rs8099917) in 115 chronic hepatitis C genotype 1 patients who underwent pegylated-interferon-α2b (PEG-IFN) and ribavirin therapy. HLA-Bw4 was significantly associated with a sustained virological response (SVR) to treatment (P = 0.017; odds ratio [OR] = 2.50, ), as was the centromeric A/A haplotype of KIR (P = 0.015; OR 3.37). In contrast, SVR rates were significantly decreased in patients with KIR2DL2 or KIR2DS2 (P = 0.015; OR = 0.30, and P = 0.025; OR = 0.32, respectively). Multivariate logistic regression analysis subsequently identified the IL28B TT genotype (P = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01), KIR2DL2/HLA-C1 (P = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75), KIR3DL1/HLA-Bw4 (P = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05), and white blood cell count at baseline (P = 0.009; OR = 3.32, 95% CI = 1.35 - 8.16) as independent predictive factors of an SVR. We observed a significant association between the combination of IL28B TT genotype and KIR3DL1-HLA-Bw4 in responders (P = 0.0019), whereas IL28B TT along with KIR2DL2-HLA-C1 was related to a non-response (P = 0.0067). In conclusion, combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV. 相似文献
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Caggiari L Toffoli G De Re V Orzes N Spina M De Zorzi M Maiero S Cannizzaro R Canzonieri V 《The International journal of biological markers》2011,26(4):221-228
The pathogenesis of celiac disease (CD) is associated with polymorphisms in human leukocyte antigen (HLA) genes; however, compelling evidence suggests that additional non-HLA genes are associated with CD and related complications. The present study investigated whether killer cell immunoglobulin-like receptor (KIR)/HLA gene combinations are associated with CD and its clinical complications in the population of northeast Italy. The study included 61 adults affected by CD: 48 patients were at first diagnosis and 13 patients had CD-related complications (8 with refractory CD and 5 with cancer). Controls were 69 blood donors genotyped for KIR and HLA. Several statistically significant differences emerged between CD patients and blood donors. The results herein presented show that susceptibility to CD with refractory disease or cancer is associated with various genotypes including the 2DS2/2DL2+C1, 2DS3, 3DL1, and 2DL5B genes. In addition, the absence of the Bw4 ligand may be a predisposing factor for cancer. These results suggest that a KIR haplotype and HLA ligands may be involved in the susceptibility to important clinical CD complications such as tumors or refractoriness as a result of a gluten-free diet. 相似文献
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David Palesch Mohammad Khalid Christina M. Stürzel Jan Münch 《Applied and environmental microbiology》2014,80(8):2617-2622
Xenotropic murine leukemia virus-related virus (XMRV) represents a novel γ-retrovirus that is capable of infecting human cells and has been classified as a biosafety level 2 (BSL-2) organism. Hence, XMRV represents a potential risk for personnel in laboratories worldwide. Here, we measured the stability of XMRV and its susceptibility to alcohol-based disinfectants. To this end, we exposed an infectious XMRV reporter virus encoding a secretable luciferase to different temperatures, pH values, and disinfectants and infected XMRV-permissive Raji B cells to measure residual viral infectivity. We found that 1 min treatment of XMRV particles at 60°C is sufficient to reduce infectivity by 99.9%. XMRV infectivity was maximal at a neutral pH but was reduced by 86% at pH 4 and 99.9% at pH 10. The common hand and surface disinfectants ethanol and isopropanol as well as the cell fixation reagent paraformaldehyde abrogated XMRV infectivity entirely, as indicated by a reduction of infectivity exceeding 99.99%. Our findings provide evidence of specific means to inactivate XMRV. Their application will help to prevent unintended XMRV contamination of cell cultures in laboratories and minimize the risk for laboratory personnel and health care workers to become infected with this biosafety level 2 organism. 相似文献
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Background
The functions of ghrelin (GHRL) include anti-inflammatory effects, reduction of the fibrogenic response, protection of liver tissue, and regulation of cell proliferation. Genetic variations in the GHRL gene may play an important role in the development of chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Therefore, we investigated whether GHRL gene polymorphisms and its serum levels are associated with hepatitis B virus (HBV)-related diseases risk in a Chinese population.Methods
176 patients with CHB, 106 patients with HBV-related LC, 151 patients with HBV-related HCC, and 167 healthy controls were recruited in the study. Genotyping of GHRL rs26311, rs27647, rs696217, and rs34911341 polymorphisms were determined with the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing. The serum GHRL concentrations were determined using enzyme-linked immunosorbent assay (ELISA).Results
Binary logistic regression analyses adjusting for gender and age revealed that a significant increased risk of LC was found in the GHRL rs26311 GC genotype and combined GC+CC genotypes when compared with the GG genotype (GC vs. GG: OR = 1.671, 95% CI = 1.013–2.757, P = 0.044; GC+CC vs. GG: OR = 1.674, 95% CI = 1.040–2.696, P = 0.034). In subgroup analysis by gender, binary logistic regression analyses adjusting for age showed that the GHRL rs26311 C allele and combined GC+CC genotypes were associated with a significantly increased risk to LC in males (C vs. G OR = 1.416, 95% CI = 1.017–1.972, P = 0.040; GC+CC vs. GG: OR = 1.729, 95% CI = 1.019–2.933, P = 0.042). In addition, we found significant decreased serum GHRL levels in LC patients compared with the healthy controls. However, there was no significant association of the GHRL rs26311 polymorphism with serum GHRL levels in LC patients.Conclusions
These observations suggest that the GHRL rs26311 polymorphism is associated with an increased risk to HBV-related LC, especially in men. We also found an inverse association of serum GHRL levels with LC. 相似文献19.
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Hariklia Eleftherohorinou Victoria Wright Clive Hoggart Anna-Liisa Hartikainen Marjo-Riitta Jarvelin David Balding Lachlan Coin Michael Levin 《PloS one》2009,4(11)
Although the introduction of genome-wide association studies (GWAS) have greatly increased the number of genes associated with common diseases, only a small proportion of the predicted genetic contribution has so far been elucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementary approach to the more common single SNP association approach in understanding genetic determinants of common disease. We developed a novel pathway-based method to assess the combined contribution of multiple genetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases. We tested inflammatory pathways for association with Crohn''s disease (CD), rheumatoid arthritis (RA) and type 1 diabetes (T1D) with 4 non-inflammatory diseases as controls. Using a variable selection algorithm, we identified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation framework in order to calculate out-of-sample area under the Receiver Operating Curve (AUC). The generalisability of these predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical inflammatory pathways showed highly significant associations (p 10−3–10−20) with CD, T1D and RA. Variable selection identified on average a set of 205 SNPs (149 genes) for T1D, 350 SNPs (189 genes) for RA and 493 SNPs (277 genes) for CD. The pattern of polymorphisms at these SNPS were found to be highly predictive of T1D (91% AUC) and RA (85% AUC), and weakly predictive of CD (60% AUC). The predictive ability of the T1D model (without any parameter refitting) had good predictive ability (79% AUC) in the Finnish cohort. Our analysis suggests that genetic contribution to common inflammatory diseases operates through multiple genes interacting in functional pathways. 相似文献