RESUMEN
Multidrug resistance gene 1 (MDR1) is known for its involvement in the detoxification through the active transport of toxic compounds from diverse origins outside the cells. These compounds could cause injury to cell DNA, which might lead in cancer like chronic myeloid leukemia (CML). Individual inherited genetic differences related to polymorphism in detoxification enzymes could be an important factor not only in carcinogen metabolism but also in susceptibility of cancer. The present study aimed to investigate the association of three single nucleotide polymorphisms (SNPs) of the MDR1 gene in the susceptibility of CML. We successively have determined the genotype profiles of 1236 C>T (exon 12); 2677 G>T (exon 21), and 3435 C>T (exon 26) SNPs by PCR-RFLP in 89 patients and 99 unrelated healthy controls. Logistic regression was used to assess the effect of each SNP on the development of CML. Interestingly, in exon 12, the 1236 TT was significantly associated with the susceptibility of CML when compared to the wild type 1236 CC (OR 2.7; 95% CI 1-7.32, p = 0.041). Additionally, the recessive model 1236 TT vs. 1236 CC/CT showed a risk of 3.3 fold (p = 0.011) with CML. In exon 26, the 3435 CT genotype was associated with a reduced risk of CML (OR 0.5; 95% CI 0.3-1, p = 0.042). In exon 21, the 2677 GT genotype seems to have a protective effect (OR 0.6; 95% CI 0.32-1.1, p = 0.074). Diplolotypes analysis has demonstrated no effect in susceptibility of CML, but 1236 CT/3435 CC and 1236 CC/2677 GT were associated with a protective effect. The haplotypes analysis showed no particular trend (global association p = 0.33). Our findings demonstrate that 1236 TT in exon 12 might contribute in the susceptibility of CML, while the 3435 CT in exon 26 as well as 1236 CT/3435 CC and 1236 CC/2677 GT combinations might be protective factors.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Polimorfismo de Nucleótido Simple/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Genotipo , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Factores de Riesgo , Adulto JovenRESUMEN
INTRODUCTION: The multidrug resistance 1 (MDR1) gene plays an important function in carcinogens detoxification and drugs metabolism. Many authors reported that MDR1 gene influences individual susceptibility to cancers. We carried out the present case-control study to investigate the impact of MDR1 gene in the predisposition to acute myeloid leukemia (AML) in a sample of Moroccan population. In addition, we performed a meta-analysis study to discuss our results and to better highlight the influence of MDR1 gene on the susceptibility of AML. METHODS: The study included 187 AML patients and 206 controls. Genomic DNA was extracted from white blood cell by salting method. Polymorphisms of G2677 T and C3435 T were genotyped by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), using Mbo I and Ban I restriction enzymes. Statistical analysis was performed using the software SPSS (version 19.0; SPPS Inc., Chicago, IL, USA) and MedCalcv.11.6.1.0 software. RESULTS: No statistically significant differences in genotype and allelic distribution were found in G2677 T and C3435 T polymorphisms between AML cases and controls in the Moroccan population. On the other hand, we found that the age of onset of AML in patients with homozygous mutant genotype was statistically lower than in patients with either the heterozygous or wild type genotype for both polymorphisms (P = 0.006; P = 0.03). Meta-analysis showed a significant association of C3435 T, G2677 T polymorphisms on the susceptibility of AML when considering the recessive and the allelic models. CONCLUSION: Our findings showed that the G2677 T and C3435 T polymorphisms of the MDR1 gene were associated with the age at onset of AML in our population. In addition, the meta-analysis showed that these polymorphisms could play a role in susceptibility to AML.
Asunto(s)
Genes MDR , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleótido Simple , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , ADN de Neoplasias/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Marruecos/epidemiología , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Adulto JovenRESUMEN
Nitric oxide plays a major role in the regulation of cerebral blood flow and loss of its function leads to alteration of the vascular relaxation given its central role in the physiology of the vascular system. G894T eNOS polymorphism could have adverse effects on the expression and activity of endothelial nitric oxide synthase, which can result in functional impairment of the endothelium and contribute to the development of ischemic stroke in the different models of transmission. In this study, genotyping with PCR-RFLP and HRM (high resolution melting) methods were conducted on 165 ischemic stroke patients as well as 182 controls. The goal here was to compare genotyping with PCR-RLFP primer sequences of eNOS gene (size < 300 bp) to HRM. Our data suggests a statistically significant association between G894T eNOS polymorphism and ischemic stroke in recessive, dominant and additive models with P < 0.05 and odds ratio of 2.68 (1.08-6.70), 1.78 (1.16-2.73), and 1.71 (1.21-2.43) respectively. In sum, although the sample size is relatively small, it suggests that G894T eNOS polymorphism could be a potentially important genetic marker of ischemic stroke in the Moroccan population. Future studies should be conducted in this direction taking into consideration the functional activity of eNOS.