RESUMEN
Ultraviolet radiation (UVR) may contribute to multiple sclerosis (MS) outcome by a mechanism involving vitamin D and the vitamin D receptor (VDR). In 512 patients with MS duration of 10 or more years, we studied the association of VDR single nucleotide polymorphisms (A/G(1229), C/G(3444), G/A(3944), CC(20965), CC(30056), F/f(30875), C/T(48200), T/t(65013)) with outcome or disability. ff(30875) frequency was lower in cases with EDSS > or = 6.0 than with scores < 6.0 (odds ratio = 0.38, 95% CI = 0.20-0.70). The association of ff(30875) with outcome was not mediated by cumulative exposure to UVR as assessed by questionnaire; low exposure (odds ratio = 0.42, 95% CI = 0.14-1.34) and high exposure (odds ratio = 0.34, 95% CI = 0.16-0.73).
Asunto(s)
Evaluación de la Discapacidad , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Receptores de Calcitriol/genética , Rayos Ultravioleta , Adulto , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Haplotipos , Humanos , Modelos Logísticos , Masculino , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/fisiopatología , Factores de Riesgo , Adulto JovenRESUMEN
Susceptibility and outcome in complex disorders such as asthma and cancer appear to be determined, at least in part, by genetic polymorphism. However, while our ability to identify new allelic variants and study them in case and control populations has greatly improved, considerable difficulties remain in elucidating how many genes determine particular clinical phenotypes. This is because most studies have concentrated on study of single genes in relatively small study groups. The important issues of gene-gene interactions (epistasis) and high-risk subgroups have not yet been adequately addressed. We now describe a general approach, using patients with head and neck cancers as an example. Our purpose is to demonstrate candidate gene selection, statistical approaches, and identification of patient subgroups.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Neoplasias de Cabeza y Cuello/genética , Polimorfismo Genético , Humanos , Epidemiología Molecular , Herencia Multifactorial , Factores de RiesgoRESUMEN
OBJECTIVE: To determine whether polymorphism in the manganese superoxide dismutase (MnSOD) gene is associated with susceptibility or disease outcome in rheumatoid arthritis (RA). METHODS: We used a case-control approach with 153 RA patients and 218 control subjects to examine for any associations between MnSOD genotypes and susceptibility to RA. We also investigated the influence of genotypes on radiologic outcome, as measured using the Larsen score for radiographs of the hands and feet, and on functional outcome, as assessed by the Health Assessment Questionnaire. MnSOD typing was carried out using polymerase chain reaction-based methods. Results were analyzed using multiple regression analysis, with adjustment for age, sex, and disease duration. In separate analyses, we corrected for rheumatoid factor (RF) status and/or the presence of the HLA-DRB1 "shared epitope" (SE). We also examined whether radiologic outcome was influenced by interactions between MnSOD and glutathione S-transferase (GST) genes. RESULTS: No association between MnSOD genotype and development of RA was found. The MnSOD VV genotype was associated with a significantly higher (P = 0.04) Larsen score (104.4) than MnSOD AA (83.0), while MnSOD AV was associated with an intermediate score (91.8). Correction for RF status had no significant effect on the results of the analysis, but significance was lost (P = 0.09) after correction for the presence of the SE. There was evidence of interaction between the GSTT1 and MnSOD genotypes, with the MnSOD VV/GSTT1-null combination being associated with the highest Larsen score (142.1; P = 0.007 after correction for the SE). CONCLUSION: Polymorphism in the MnSOD gene is not associated with susceptibility to RA. Our data suggest that MnSOD VV is associated with more severe radiologic outcome, although this relationship may not be independent of the effect of the SE. However, interaction between MnSOD and GST genes appears to influence radiologic outcome independently of the SE.
Asunto(s)
Artritis Reumatoide/genética , Superóxido Dismutasa/genética , Anciano , Artritis Reumatoide/diagnóstico , Interacciones Farmacológicas/genética , Femenino , Marcadores Genéticos/fisiología , Predisposición Genética a la Enfermedad , Genotipo , Glutatión Transferasa/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Especies Reactivas de Oxígeno/fisiologíaRESUMEN
BACKGROUND: Oxidative stress has been implicated in inflammatory demyelination. The glutathione S-transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress. Certain GST loci are polymorphic, demonstrating alleles that are null (GSTM1/GSTT1), encode low activity variants (GSTP1), or are associated with variable inducibility (GSTM3). OBJECTIVES: To investigate the association between clinical outcome in MS and allelic variants of GSTM1, GSTM3, GSTT1, and GSTP1. METHODS: Four hundred patients with clinically definite MS were studied. Disability was measured using the Kurtzke Expanded Disability Status Scale (EDSS). Disability was graded as mild (EDSS 0-4), moderate (4.5-5.5), or severe (EDSS 6-10). PCR-based genotyping was performed using DNA extracted from lymphocytes. Significant associations between GST genotypes and clinical outcome were corrected for gender, onset age, and disease duration using logistic regression. RESULTS: We found that the GSTM3 AA genotype was associated with severe disability in patients with a disease duration of more than 10 years (p = 0.027, n = 177, OR = 2.4, 95% CI = 1.1-5.0). Homozygosity for both GSTM1*0 and GSTP1*Ile105 containing allele was associated with severe disability in patients with a disease duration greater than 10 years (p = 0.022, n = 179, OR = 5.0, 95% CI = 1.3-19.8). CONCLUSIONS: Our results suggest that long-term prognosis in MS is influenced by a genetically determined ability to remove the toxic products of oxidative stress.
Asunto(s)
Evaluación de la Discapacidad , Glutatión Transferasa/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/fisiopatología , Polimorfismo Genético/genética , Adulto , Edad de Inicio , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
GST, CYP, and CCND1 genotypes have been associated with outcome in several cancers. Accordingly, we have examined, in patients with one squamous cell carcinoma (SCC) of the head and neck, associations between GSTM1, GSTT1, GSTM3, GSTP1, CYP2D6, CYP1A1, CYP2E1, and CCND1 genotypes and the outcome parameters, tumor extension, histological grade, and presence of nodes. We used logistic regression to study, first, each gene individually and, second, in a step-wise model that included all of the genes. Different genes were associated with each outcome parameter. Thus, GSTT1 null was associated with T3/T4 lesions in the oral cavity/pharyngeal (P = 0.029), but not laryngeal, SCC cases. GSTT1 null was also associated with histological differentiation (G3) in the oral cavity/pharyngeal, but not laryngeal, SCC cases, although this association only approached significance (P = 0.069). CCND1 GG was associated with G3 tumors in the oral cavity/pharyngeal (P = 0.011), but not laryngeal, SCC cases. The combination of GSTT1 null/CCND1 GG was also associated with G3 tumors. CYP2D6 PM and HET were associated with lymph node involvement in the laryngeal, but not oral/pharynx, SCC cases. Genes that were individually associated with outcome were also associated with the parameter in the step-wise routine. The GSTT1 null frequency was greater in 39 patients with second primary tumors than in those with one lesion (P = 0.014). The data demonstrate site-dependent associations between GSTT1 null, CCND1 GG, and CYP2D6 PM and tumor extension, differentiation, and nodes.
Asunto(s)
Carcinoma de Células Escamosas/genética , Ciclina D1/genética , Sistema Enzimático del Citocromo P-450/genética , Glutatión Transferasa/genética , Neoplasias Laríngeas/genética , Neoplasias Orofaríngeas/genética , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Femenino , Genotipo , Alemania/epidemiología , Humanos , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/patología , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVE: To determine whether glutathione S-transferase GSTM1, GSTM3, GSTT1, and GSTP1 genotypes influence susceptibility or outcome in rheumatoid arthritis (RA). METHODS: 277 RA patients were compared with 577 controls to examine any associations between GST genotypes and susceptibility to RA. The effect of genotypes on outcome (Larsen and functional scores) and time integrated acute phase responses (erythrocyte sedimentation rate and C reactive protein) was assessed in 122 patients with disease duration of 5-10 years. GST and HLA-DRB1 genotypes were determined using polymerase chain reaction based assays. Data were analysed using multiple regression analysis with correction for age, sex, disease duration, and the DRB1 associated shared epitope (SE) and rheumatoid factor (RF) positivity where appropriate. RESULTS: The GSTM1*A/*B genotype was less common in RA cases (3 of 276) than in controls (22 of 591) (exact p = 0.047), though significance was lost when adjustment was made for multiple comparisons. The Larsen score was higher (p = 0.039) in the GSTM1 null patients (89.9) than those with other GSTM1 genotypes (74.7), and this was independent of the SE. Again, correction for multiple testing resulted in loss of significance. The difference in Larsen scores between patients homozygous or negative for the SE (87.9 v 74.3) was similar to that between GSTM1 null and non-null patients. No associations between GSTM3 or GSTT1 genotypes and disease markers were identified although the association between GSTP1*B/*B and Larsen score approached significance (p = 0.096). CONCLUSION: It is proposed that certain GSTs may influence susceptibility and radiological progression in RA and that this is independent of the effect of the HLA-DRB1 associated SE. The mechanism for this effect is presumed to be because of differences in the ability of various GST enzymes to utilise the cytotoxic products of oxidant stress. Although significance was lost after correction for multiple testing, the data indicate that further studies may be of value in RA to determine the influence of the GST and other genes involved in cellular protection against oxidative stress.
Asunto(s)
Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Polimorfismo Genético , Reacción de Fase Aguda , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/inmunología , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Genotipo , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de RegresiónRESUMEN
OBJECTIVES: To investigate whether the therapeutic response of rheumatoid arthritis (RA) patients to D-penicillamine is associated with polymorphisms in genes of the glutathione S-transferase (GST) supergene family. METHODS: Disease activity in 81 patients with RA treated with D-penicillamine monotherapy was assessed using the Stoke Index, a validated index of disease activity, prior to treatment and at 6 months. GST typing was performed using a polymerase chain reaction-based approach and a logistic regression model was used to investigate any possible association between the therapeutic response to D-penicillamine and the GST genotype. RESULTS: A poor therapeutic response was associated with the GSTM1 null genotype [odds ratio (OR) 3.94], and in particular with the GSTM1*0/GSTM3*A haplotype (OR 7.63). CONCLUSIONS: Our results suggest that GST polymorphisms may influence the response to D-penicillamine in RA, and that patients in possession of the GSTM1*0/GSTM3*A haplotype are significantly less likely to show a beneficial response to the drug.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Glutatión Transferasa/genética , Penicilamina/uso terapéutico , Polimorfismo Genético , Artritis Reumatoide/enzimología , Femenino , Genotipo , Haplotipos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Factor Reumatoide/sangre , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Epithelial ovarian cancer is generally associated with a poor outcome, although the mechanisms that determine survival and progression-free interval (PFI) are unclear. Data from ovarian tumors showing associations between (a) null genotypes at the glutathione S-transferase GSTM1 and GSTT1 loci and expression of p53 protein and (b) outcome and expression of p53 suggest that polymorphism at these loci is a factor determining outcome. Accordingly, we have studied the association between the GSTM1 null and GSTT1 null genotypes and survival and PFI in 148 women with epithelial ovarian cancer. Although we did not find an association between individual genotypes and outcome, women with both GSTM1 null and GSTT1 null genotypes demonstrated poorer survival (P = 0.001) and reduced PFI (P = 0.003). Thus, no cases with both these genotypes survived past 42 months postdiagnosis. In contrast, 43% of the women without this combination survived beyond this time. Because response to chemotherapy is a major factor determining outcome in ovarian cancer, we also examined the data for associations between the glutathione S-transferase genotypes and response to such treatment. Thus, in 78 patients treated with chemotherapy, the combination of GSTM1 null and GSTT1 null was associated with unresponsiveness to primary chemotherapy (P = 0.004); none of the eight patients with both these genotypes responded, compared with 38 of 70 (54%) of patients with other genotype combinations. The effect of the combination of genotypes on survival and PFI was lost in a multivariate model that included response to chemotherapy as a confounding factor. This suggests that the combination of GSTM1 null/GSTT1 null is associated with outcome because of its influence on response to chemotherapy. These preliminary findings may provide a basis for the selection of patients for treatment with chemotherapeutic agents.
Asunto(s)
Glutatión Transferasa/genética , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Ováricas/tratamiento farmacológicoRESUMEN
We have examined the hypothesis that the polymorphic, glutathione S-transferase GSTP1 gene is a susceptibility candidate for squamous cell cancer of the oral/pharynx and larynx. We describe GSTP1 genotype frequencies in 380 cases and 180 controls. We found a lower frequency of GSTP1 AA in the oral/pharyngeal cases compared with controls (p = 0.003, odds ratio = 0.47) after correction for age and gender. We used an immunohistochemical approach to show widespread expression of the GSTP1 subunit throughout the pharynx and larynx. In uninfiltrated tissue, strong positivity was found throughout the squamous cell epithelium with the exception of the basal cell layer. The cilia of the respiratory epithelium of the larynx also showed positivity for GSTP1. In tumour tissue, expression of GSTP1 was similar in pharyngeal and laryngeal samples. These data are the first to show that polymorphism at GSTP1 mediates susceptibility to squamous cell cancer of the upper aerodigestive tract. No significant interactions were identified between GSTP1 and GSTM1, GSTM3, GSTT1 and the cytochrome P450 CYP1A1, CYP2D6 and CYP1A1 genotypes.
Asunto(s)
Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Glutatión Transferasa/genética , Isoenzimas/genética , Neoplasias Laríngeas/enzimología , Neoplasias Laríngeas/genética , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/genética , Neoplasias Faríngeas/enzimología , Neoplasias Faríngeas/genética , Polimorfismo Genético , Consumo de Bebidas Alcohólicas/efectos adversos , Carcinoma de Células Escamosas/etiología , Estudios de Casos y Controles , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2E1/genética , Femenino , Frecuencia de los Genes , Genotipo , Gutatión-S-Transferasa pi , Glutatión Transferasa/química , Humanos , Inmunohistoquímica , Isoenzimas/química , Neoplasias Laríngeas/etiología , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/etiología , Oportunidad Relativa , Neoplasias Faríngeas/etiología , Conformación Proteica , Fumar/efectos adversosRESUMEN
Glutathione S-transferase GSTM1, GSTM3 and GSTT1 and cytochrome P450 CYP2D6, CYP1A1 and CYP2E1 loci are susceptibility candidates for cancers of the upper aerodigestive tract because putatively protective and risk genotypes have been identified from studies in other diseases associated with alcohol and tobacco consumption. We describe genotype frequencies in 398 oral, pharyngeal and laryngeal squamous cell carcinoma patients and 219 control individuals. Of the genotypes presumed to be protective, only GSTM1 A/B influenced susceptibility; the GSTM1 A/B frequency was lower in the patients than the control individuals both before [odds ratio = 0.3, 95% confidence interval (CI) 0.1-0.7] and after correction for imbalances in age, sex, smoking and alcohol consumption (odds ratio = 0.2, 95% CI 0.1-0.5). Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, was higher in the cases (odds ratio = 1.6, 95% CI 1.1-2.4). Dividing cases into oral/pharyngeal and laryngeal squamous cell carcinoma showed the GSTM3 AA frequency was higher in laryngeal squamous cell carcinoma than control individuals (odds ratio = 1.6, 95% CI 1.1-2.5) and the difference between control individuals and oral/pharyngeal squamous cell carcinoma approached significance (odds ratio = 1.7, 95% CI 1.0-2.8). The putatively protective GSTM3 BB genotype was lower in patients with glottic (1.0%) than supraglottic (3.0%) squamous cell carcinoma. We identified no differences between patients and control individuals in the frequencies of presumed risk genotypes (e.g. CYP2D6 EM, CYP1A1 m1/m1, CYP1A1 Ile/Ile, CYP2E1 DD, CYP2E1 c1c1, GSTT1 null) or, interactions between genotypes and smoking or alcohol consumption. We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk. The influence of GSTM1 A/B, but not GSTM1 A or GSTM1 B (mostly heterozygotes with GSTM1*0) suggests that two expressed alleles may attenuate risk. While we found immunohistochemical evidence of GSTM3 expression in the cilia lining the larynx, the biochemical consequences of the polymorphism are unclear. Indeed, the influence of the gene may reflect linkage disequilibrium with another gene. However, we did not find an association with GSTM1 genotypes. Second, we conclude that the CYP2D6, CYP2E1, CYP1A1 and GSTT1 alleles studied, although putatively good candidates, either do not determine the effectiveness of detoxification of tobacco-derived carcinogens in the upper aerodigestive tract or, that chronic consumption of tobacco and alcohol overwhelms enzyme defences, irrespective of genotype.
Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Glutatión Transferasa/genética , Neoplasias Laríngeas/genética , Neoplasias de la Boca/genética , Neoplasias Faríngeas/genética , Fumar/efectos adversos , Anciano , Secuencia de Bases , Carcinoma de Células Escamosas/genética , Cartilla de ADN , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Inmunohistoquímica , Isoenzimas/genética , Masculino , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
Basal cell carcinoma (BCC) is the commonest cancer in Caucasians. Its incidence is rising and many patients develop multiple primary tumours at separate sites. Factors determining time between first primary tumour presentation and the next new primary lesion are unclear. We used Cox's proportional hazards model to study, in 856 Caucasians, the influence of tumour site, individual characteristics and polymorphism in glutathione S-transferase (GSTM1, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) loci on time to next primary tumour presentation. More than one tumour at first presentation (P <0.0001, hazard ratio 2.72) and GSTT1 null (P = 0.028, hazard ratio 1.74) were associated with decreased time to next primary tumour presentation. Significant two-factor interactions, corrected for number of tumours at presentation, were identified between a truncal tumour at first presentation and each of male gender, GSTM1 null and CYP2D6 EM (P <0.003, hazard ratios 3.09-3.82). In each of these cases, all patients with the risk combination demonstrated further separate tumours within 5 years of first presentation. Thus, patients with a truncal tumour at first presentation, especially males and those presenting with more than one lesion have a significantly decreased time to presentation of further tumours and should receive more meticulous follow-up. Polymorphism in GSTM1 and CYP2D6 also influences the rate of new primary tumour accrual giving insights into the link between ultraviolet exposure and multiple tumour development.
Asunto(s)
Carcinoma Basocelular/epidemiología , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP2D6/genética , Glutatión Transferasa/genética , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Cutáneas/epidemiología , Anciano , Carcinoma Basocelular/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores Sexuales , Neoplasias Cutáneas/genética , Factores de TiempoRESUMEN
Basal cell carcinoma (BCC) places increasing burdens on clinicians; incidence is rising and patients may develop multiple primary tumors. Although UV exposure is critical, many patients develop tumors at less-exposed sites, such as the trunk, suggesting a genetic predisposition. We previously showed that polymorphism in loci encoding the detoxifying enzymes, glutathione S-transferase (GSTM1, GSTM3, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) influences susceptibility to BCC. We now describe a case-control approach in 345 patients with BCC that examines the role of these polymorphisms and patient characteristics (age, gender, skin type, hair color, eye color, smoking, occupation) in determining susceptibility to truncal tumors. GST and CYP genotypes were identified using polymerase chain reaction-based methods. Patients with one or more truncal tumors were significantly younger (p = 0.0170) than those with no truncal tumors. Male gender also appeared more common in the truncal tumor group, although this did not achieve significance (p = 0.0925). Patients whose first tumor was truncal had significantly more tumors (p = 0.0297). GSTT1 null (p = 0.0245, odds ratio 2.24) and CYP1A1 Ile/Ile (p = 0.0386, odds ratio 2.86) were associated with truncal site after correction for age and gender. The combination, GSTT1 null and CYP1A1 Ile/Ile, was particularly significant (p = 0.0059, odds ratio = 2.95). These effects were present after correction for tumor numbers. These data show first, patients with truncal tumors constitute a high-risk group for BCC, second, a significant genetic influence on BCC site, and third, a significant interaction between GSTT1 and CYP1A1 genotypes.
Asunto(s)
Carcinoma Basocelular/epidemiología , Citocromo P-450 CYP1A1/genética , Sistema Enzimático del Citocromo P-450/genética , Glutatión Transferasa/genética , Isoenzimas/genética , Neoplasias Torácicas/epidemiología , Anciano , Carcinoma Basocelular/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Neoplasias Torácicas/genéticaAsunto(s)
Autoantígenos/inmunología , Glutatión Transferasa/genética , Lupus Eritematoso Sistémico/enzimología , Lupus Eritematoso Sistémico/inmunología , ARN Citoplasmático Pequeño , Ribonucleoproteínas/inmunología , Alelos , Autoanticuerpos/sangre , Autoantígenos/sangre , Homocigoto , Humanos , Mutación/inmunología , Fenotipo , Trastornos por Fotosensibilidad/enzimología , Trastornos por Fotosensibilidad/inmunología , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Ribonucleoproteínas/sangreRESUMEN
The genetic factors that mediate the pathogenesis of multiple primary cutaneous basal cell carcinomas (BCC) are largely unclear. Thus, some patients suffer many BCC (>30) and/or rapid accrual (number of tumours/year from first presentation) of further lesions. We have studied, in 827 English Caucasians, the influence of polymorphism in carcinogen-metabolizing enzymes on susceptibility to this cancer. Accordingly, we describe, first, a cross-sectional analysis of the influence of GSTM1, GSTT1, CYP2D6 and CYP1A1 genotypes on tumour numbers, and secondly, a longitudinal analysis, in 169 of these cases, of the effect of these genes on tumour accrual. We have confirmed the expected importance of age and number of lesions at presentation, and male gender and skin type as risk factors. Furthermore, the cross-sectional analysis showed CYP1A1 m1m1 (P = 0.004; rate ratio 1.242) and CYP2D6 EM (P < 0.001, rate ratio 1.266) are associated with increased numbers of BCC. The longitudinal study showed, after adjustment for age and tumour number at presentation, that GSTT1 null (P < 0.001, rate ratio 2.677) and CYP2D6 EM (P < 0.001, rate ratio 2.154) were significant determinants of accrual while CYP1A1 Ile/Ile was associated with slower accrual than the Ile/Val and Val/Val genotypes (P = 0.008, rate ratio 0.690). We believe these are the first genetic factors to be associated with tumour accrual. No significant interactions between genotypes were identified, though the combinations GSTM1 null/skin type 1 (P < 0.001, rate ratio 2.702), CYP2D6 EM/male gender (P = 0.049, rate ratio 1.279) and CYP2D6 EM/blue+green eyes (P = 0.046, rate ratio 1.388) influenced tumour numbers. Previous studies indicate the importance of effective repair of UV-damaged DNA in the pathogenesis of multiple BCC; indeed the influence of GSTM1 may result from its ability to utilize 5'-hydroxymethyluracil. However, the finding that CYP2D6 and CYP1A1 influence tumour numbers and accrual indicates detoxification of unknown molecules is important and supports the view that factors other than UV are important in the pathogenesis BCC.
Asunto(s)
Carcinoma Basocelular/genética , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP2D6/genética , Glutatión Transferasa/genética , Isoenzimas/genética , Polimorfismo Genético , Neoplasias Cutáneas/genética , Adulto , Anciano , Carcinoma Basocelular/patología , Estudios Transversales , Inglaterra , Color del Ojo , Femenino , Genotipo , Humanos , Estudios Longitudinales , Masculino , Caracteres Sexuales , Neoplasias Cutáneas/patología , Pigmentación de la Piel , Fumar , Población BlancaRESUMEN
We describe studies to assess the influence of polymorphism in the human glutathione S-transferase GSTM3 gene on susceptibility to high grade astrocytoma. Immunohistochemical studies using a GSTM3-specific antiserum identified expression of the GSTM3 subunit in astrocytes. The relative levels of expression of GSTM1 and GSTM3 in brain cytosols were determined after resolution of these enzymes using chromatofocusing. We found no differences in the level of GSTM3 activity in individuals with GSTM1 null and those with GSTM1-positive genotypes (GSTM1 A, GSTM1 B and GSTM1 A/B). A case-control study was performed to determine if GSTM3 alone or in combination with GSTM1 or GSTT1 influenced susceptibility to high grade astrocytoma. After correction for differences in age and gender, GSTM3 AA was not significantly different in cases compared with controls. No significant interactions between GSTM3 AA and GSTM1 null were identified. The significant interaction between GSTM3 AA and GSTT1 null appeared to result from the strength of the main effect (GSTT1 null). The data show that while GSTM3 is expressed in astrocytes and contributes significantly to total GST activity in human brain, it does not appear to influence susceptibility to high grade astrocytoma. Further, unlike lung, there appears to be no relationship between the level of GSTM3 activity in brain and GSTM1 genotype.
Asunto(s)
Astrocitoma/epidemiología , Astrocitoma/genética , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/genética , Encéfalo/enzimología , Glutatión Transferasa/genética , Isoenzimas/genética , Alelos , Astrocitoma/patología , Secuencia de Bases , Encéfalo/patología , Neoplasias Encefálicas/patología , Citosol/enzimología , Frecuencia de los Genes , Genotipo , Humanos , Factores de RiesgoRESUMEN
The influence of polymorphism in the glutathione S-transferase, GSTM3 gene on susceptibility to cutaneous basal cell carcinoma (BCC) has been investigated. We have reported previously two GSTM3 alleles, GSTM3*A and GSTM3*B, distinguished by a recognition motif for the YY1 transcription factor in GSTM3*B. In this study, immunohistochemistry was used to identify GSTM3 expression in the epidermis of skin samples from 11 controls and 9 patients with BCC. A PCR method was used to identify GSTM3*A and GSTM3*B and thereby the GSTM3 AA, GSTM3 AB, and GSTM3 BB genotypes in 300 controls and 286 Caucasians with 1-35 primary BCCs. Genotypes at GSTM1, GSTT1, and the cytochrome P450 CYP1A1 and CYP2D6 loci were also determined. Frequencies of GSTM3, GSTM1, GSTT1, CYP2D6, and CYP1A1 genotypes in the cases and controls were not different. Dividing the BCC cases into groups of 92 patients with 1 lesion and 194 patients with 2-35 lesions showed that the frequencies of GSTM3 BB (2.6%) and GSTM1 A/B (1.3%) in the group with 2-35 tumors were almost significantly lower than in the group with 1 lesion (7.6%, exact P = 0.0601, chi 2(1) = 3.390; 6.5%, exact P = 0.055, chi 2(1) = 4.946, respectively). Within the cases with 2-35 tumors, a Poisson regression model was used to identify genotypes, characteristics such as skin type, and interactions between genotypes and characteristics associated with increasing numbers of tumors. This showed, after correction for male gender and age, that GSTM3 AA was not associated with risk of increased numbers of tumors, although in combination with skin type 1, GSTM1 null, and CYP1A1 m1m1, the genotype did confer increased risk (P < 0.001, rate ratio, 2.058; P < 0.001, rate ratio, 1.606; P < 0.001, rate ratio, 1.470 respectively). The data suggest that, like other allelic GST, GSTM3 influences cancer risk. As GSTM3 AA was associated with increased tumor numbers, it appears that YY1 acts as an activator of the recognition motif in GSTM3*B.
Asunto(s)
Carcinoma Basocelular/genética , Sistema Enzimático del Citocromo P-450/genética , Glutatión Transferasa/genética , Neoplasias Primarias Múltiples/genética , Polimorfismo Genético , Neoplasias Cutáneas/genética , Anciano , Alelos , Carcinoma Basocelular/enzimología , Femenino , Genotipo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/enzimología , Factores de Riesgo , Neoplasias Cutáneas/enzimologíaAsunto(s)
Enzimas/genética , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Antioxidantes/metabolismo , Carcinoma Basocelular/enzimología , Carcinoma Basocelular/genética , Femenino , Glutatión Transferasa/genética , Humanos , Masculino , Fenotipo , Polimorfismo Genético , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Allelism in glutathione S-transferase GSTM1 and GSTT1 has been suggested as a risk factor in various cancers. Accordingly, we describe a group of case-control studies carried out to identify associations between GSTT1 genotypes and susceptibility to lung, oral, gastric and colorectal cancers. The frequencies of the putatively high risk GSTT1 null genotype were not increased in the lung, oral or gastric cancer cases compared with controls but the frequency of this genotype was significantly increased (P = 0.0011, odds ratio = 1.88) in the colorectal cancer cases. No significant interactions between the GSTT1 and GSTM1 null genotypes types were identified in the cancer groups studied. Indeed, no significant associations between GSTM1 genotypes and susceptibility were identified though further evidence was obtained that the protective effect of GSTM1*A and GSTM1*B is not equal. The data complement studies showing that GSTT1 null is associated with an increased susceptibility to total ulcerative colitis and suggests that this enzyme is important in the detoxification of unidentified xenobiotics in the large intestine.
Asunto(s)
Glutatión Transferasa/genética , Isoenzimas/genética , Neoplasias/genética , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Susceptibilidad a Enfermedades/enzimología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/epidemiología , Neoplasias de la Boca/genética , Neoplasias/enzimología , Neoplasias/epidemiología , Factores de Riesgo , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/genéticaRESUMEN
The factors that determine development of single and multiple primary cutaneous basal cell carcinomas (BCCs) are unclear. We describe a case-control study firstly, to examine the influence of allelism at the glutathione S-transferase GSTM1 and GSTT1 and cytochrome P450 CYP2D6 loci on susceptibility to these tumours and, secondly, to identify interactions between genotypes and relevant individual characteristics, such as skin type and gender. Frequency distributions for GSTM1 genotypes in cases and controls were not different, although the frequency of GSTM1 A/B was significantly lower (P = 0.048) in the multiple BCCs than in controls. We found no significant differences in the frequencies of GSTT1 and CYP2D6 genotypes in cases and controls. Interactions between genotypes were studied by comparing multinomial frequency distributions in mutually exclusive groups. These identified no differences between cases and controls for combinations of the putatively high risk GSTM1 null, GSTT1 null, CYP2D6 EM genotypes. Interactions between GSTM1 A/B and the CYP2D6 PM and GSTT1-positive genotypes were also not different. Frequency distributions of GSTM1 A/B with CYP2D6 EM in controls and multiple BCCs were significantly different (P = 0.033). The proportion of males in the multiple BCC group (61.3%) was greater than in controls (47.0%) and single BCC (52.2%), and the frequency of the combination GSTM1 null/male gender was significantly greater in patients with multiple tumours (P = 0.002). Frequency distributions of GSTM1 null/skin type 1 were also significantly different (P = 0.029) and the proportion of subjects who were GSTM1 null with skin type 1 was greater (P = 0.009) in the multiple BCC group. We examined the data for interactions between GSTM1 null/skin type 1/male gender by comparing frequency distributions of these factors in the single and multiple BCC groups. The distributions were almost significantly different (exact P = 0.051). No significant interactions between GSTT1 null or CYP2D6 EM and skin type 1 were identified. Comparisons of frequency distributions of smoking with the GSTM1 null, GSTT1 null and CYP2D6 EM genotypes identified no differences between patients with single and multiple tumours.
Asunto(s)
Carcinoma Basocelular/epidemiología , Glutatión Transferasa/genética , Isoenzimas/genética , Neoplasias Primarias Múltiples/epidemiología , Neoplasias Cutáneas/epidemiología , Fenómenos Fisiológicos de la Piel , Anciano , Alelos , Carcinoma Basocelular/enzimología , Carcinoma Basocelular/genética , Estudios de Casos y Controles , Citocromo P-450 CYP2D6 , Sistema Enzimático del Citocromo P-450/genética , Susceptibilidad a Enfermedades , Femenino , Genotipo , Humanos , Masculino , Oxigenasas de Función Mixta/genética , Neoplasias Primarias Múltiples/enzimología , Neoplasias Primarias Múltiples/genética , Factores Sexuales , Piel/enzimología , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Fumar/efectos adversos , Fumar/metabolismoRESUMEN
We describe a case-control study to identify associations between polymorphism at the cytochrome P-450 (CYP2D6) and glutathione S-transferase (GSTT1 and GSTM1) loci and susceptibility to astrocytoma and meningioma. Accordingly, genotype frequencies in 112 astrocytoma and 50 meningioma patients were compared with frequencies in 577 controls. GSTM1 genotype frequencies in these groups were not different. Logistic regression analysis showed GSTT1 null and CYP2D6 poor metabolizer were risk factors in astrocytoma (odds ratio = 2.67 P = 0.0005 and odds ratio = 4.17 P = 0.0043, respectively) and meningioma (odds ratio = 4.52, P = 0.0001 and odds ratio = 4.90, P = 0.0132, respectively) when corrected for the other variables. No interactive effects between genotypes were identified. The data suggest polymorphism at loci encoding carcinogen-metabolizing enzymes influences susceptibility to astrocytoma and meningioma, possibly by determining effectiveness in the detoxification of environmental carcinogens.