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1.
Int J Cancer ; 137(5): 1066-75, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25648508

RESUMEN

HLA genotyping and genome wide association studies provide strong evidence for associations between Human Leukocyte Antigen (HLA) alleles and classical Hodgkin lymphoma (cHL). Analysis of these associations is complicated by the extensive linkage disequilibrium within the major histocompatibility region and recent data suggesting that associations with EBV-positive and EBV-negative cHL are largely distinct. To distinguish independent and therefore potentially causal associations from associations confounded by linkage disequilibrium, we applied a variable selection regression modeling procedure to directly typed HLA class I and II genes and selected SNPs from EBV-stratified patient subgroups. In final models, HLA-A*01:01 and B*37:01 were associated with an increased risk of EBV-positive cHL whereas DRB1*15:01 and DPB1*01:01 were associated with decreased risk. Effects were independent of a prior history of infectious mononucleosis. For EBV-negative cHL the class II SNP rs6903608 remained the strongest predictor of disease risk after adjusting for the effects of common HLA alleles. Associations with "all cHL" and differences by case EBV status reflected the subgroup analysis. In conclusion, this study extends previous findings by identifying novel HLA associations with EBV-stratified subgroups of cHL, highlighting those alleles likely to be biologically relevant and strengthening evidence implicating genetic variation associated with the SNP rs6903608.


Asunto(s)
Infecciones por Virus de Epstein-Barr/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase I/genética , Enfermedad de Hodgkin/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Susceptibilidad a Enfermedades , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Cadenas HLA-DRB1/genética , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/virología , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
3.
J Feline Med Surg ; 21(10): 910-921, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30407137

RESUMEN

OBJECTIVES: The aim of this study was to evaluate a feline coronavirus (FCoV) reverse transcriptase quantitative PCR (RT-qPCR) on fine-needle aspirates (FNAs) from mesenteric lymph nodes (MLNs) collected in sterile saline for the purpose of diagnosing non-effusive feline infectious peritonitis (FIP) in cats. METHODS: First, the ability of the assay to detect viral RNA in MLN FNA preparations compared with MLN biopsy preparations was assessed in matched samples from eight cats. Second, a panel of MLN FNA samples was collected from a series of cats representing non-effusive FIP cases (n = 20), FCoV-seropositive individuals (n = 8) and FCoV-seronegative individuals (n = 18). Disease status of the animals was determined using a combination of gross pathology, histopathology and/or 'FIP profile', consisting of serology, clinical pathology and clinical signs. RESULTS: Viral RNA was detected in 18/20 non-effusive FIP cases; it was not detected in two cases that presented with neurological FIP. Samples from 18 seronegative non-FIP control cats and 7/8 samples from seropositive non-FIP control cats contained no detectable viral RNA. Thus, as a method for diagnosing non-effusive FIP, MLN FNA RT-qPCR had an overall sensitivity of 90.0% and specificity of 96.1%. CONCLUSIONS AND RELEVANCE: In cases with a high index of suspicion of disease, RT-qPCR targeting FCoV in MLN FNA can provide important information to support the ante-mortem diagnosis of non-effusive FIP. Importantly, viral RNA can be reliably detected in MLN FNA samples in saline submitted via the national mail service. When applied in combination with biochemistry, haematology and serological tests in cases with a high index of suspicion of disease, the results of this assay may be used to support a diagnosis of non-effusive FIP.


Asunto(s)
Coronavirus Felino/inmunología , Peritonitis Infecciosa Felina/diagnóstico , Peritonitis Infecciosa Felina/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Animales , Antígenos Virales/inmunología , Biopsia con Aguja Fina/veterinaria , Gatos , Ganglios Linfáticos/patología , ARN Viral/análisis , Sensibilidad y Especificidad
5.
Nat Commun ; 8(1): 1892, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29196614

RESUMEN

Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10-8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10-17), 6q23.3 (rs6928977, P = 4.62 × 10-11), 10p14 (rs3781093, P = 9.49 × 10-13), 13q34 (rs112998813, P = 4.58 × 10-8) and 16p13.13 (rs34972832, P = 2.12 × 10-8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.


Asunto(s)
Predisposición Genética a la Enfermedad , Enfermedad de Hodgkin/genética , Alelos , Estudio de Asociación del Genoma Completo , Cadenas beta de HLA-DP/genética , Cadenas HLA-DRB1/genética , Humanos , Polimorfismo de Nucleótido Simple
7.
Nat Commun ; 4: 2549, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24149102

RESUMEN

In addition to HLA, recent genome-wide association studies (GWASs) of Hodgkin's lymphoma (HL) have identified susceptibility loci for HL at 2p16.1, 8q24.21 and 10p14. In this study, we perform a GWAS meta-analysis with published GWAS (totalling 1,465 cases and 6,417 controls of European background), and follow-up the most significant association signals in 2,024 cases and 1,853 controls. A combined analysis identifies new HL susceptibility loci mapping to 3p24.1 (rs3806624; P=1.14 × 10(-12), odds ratio (OR)=1.26) and 6q23.3 (rs7745098; P=3.42 × 10(-9), OR=1.21). rs3806624 localizes 5' to the EOMES (eomesodermin) gene within a p53 response element affecting p53 binding. rs7745098 maps intergenic to HBS1L and MYB, a region previously associated with haematopoiesis. These findings provide further insight into the genetic and biological basis of inherited susceptibility to HL.


Asunto(s)
Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 6/genética , Predisposición Genética a la Enfermedad , Enfermedad de Hodgkin/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Expresión Génica , Frecuencia de los Genes , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Enfermedad de Hodgkin/etnología , Enfermedad de Hodgkin/patología , Humanos , Oportunidad Relativa , Proteínas de Dominio T Box/genética , Proteína p53 Supresora de Tumor/genética , Población Blanca
8.
J Natl Cancer Inst ; 104(3): 240-53, 2012 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-22286212

RESUMEN

BACKGROUND: Accumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification. METHODS: We conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided. RESULTS: Two novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 × 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 × 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 × 10(-4)) and replication series (P = .03). CONCLUSION: Overall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.


Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4 , Enfermedad de Hodgkin/etiología , Aminopeptidasas/metabolismo , Estudio de Asociación del Genoma Completo , Cadenas alfa de HLA-DR/metabolismo , Herpesvirus Humano 4/aislamiento & purificación , Antígenos de Histocompatibilidad Clase I/metabolismo , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/virología , Humanos , Modelos Logísticos , Antígenos de Histocompatibilidad Menor , Oportunidad Relativa , Factores de Riesgo
9.
Cancer Epidemiol Biomarkers Prev ; 20(10): 2232-6, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21859953

RESUMEN

BACKGROUND: A novel retrovirus, xenotropic murine leukemia virus-related virus (XMRV), has been detected in prostate cancer samples and in peripheral blood mononuclear cells (PBMC) from patients with chronic fatigue syndrome. In addition, the virus has been identified in PBMCs from healthy controls. These data suggest that XMRV is circulating in the human population. XMRV is closely related to murine leukemia viruses, which cause lymphoid malignancies in mice. The aim of this study was to determine whether XMRV is directly associated with common forms of human lymphoma or leukemia. METHODS: DNA samples from 368 patients with lymphoid malignancies and 139 patients with benign lymphadenopathy or other malignant disease were screened for XMRV, using three specific and sensitive quantitative PCR assays. RESULTS: XMRV was not detected in any sample using any of the three assays. CONCLUSIONS: The data suggest that this virus is not directly involved in the pathogenesis of common types of lymphoid malignancy and that XMRV is not a prevalent blood borne infection, at least in the United Kingdom. IMPACT: There is no evidence that XMRV is associated with lymphoid malignancies, and further studies should resolve inconsistencies in results of studies examining XMRV prevalence.


Asunto(s)
Leucemia/etiología , Leucocitos Mononucleares/virología , Linfoma/etiología , Infecciones por Retroviridae/complicaciones , Infecciones por Retroviridae/genética , Virus Relacionado con el Virus Xenotrópico de la Leucemia Murina/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , ADN Viral/genética , Femenino , Estudios de Seguimiento , Humanos , Lactante , Leucemia/patología , Linfoma/patología , Masculino , Persona de Mediana Edad , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Infecciones por Retroviridae/virología , Adulto Joven
10.
Nat Genet ; 42(12): 1126-1130, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21037568

RESUMEN

To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10(-8)), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10(-13)) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10(-8)). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10(-50)). These data provide new insight into the pathogenesis of cHL.


Asunto(s)
Cromosomas Humanos/genética , Factor de Transcripción GATA3/genética , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedad de Hodgkin/genética , Proteínas Proto-Oncogénicas c-rel/genética , Adulto , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 8/genética , Femenino , Genoma Humano/genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Recombinación Genética
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