MDR1 gene polymorphisms and acute myeloid leukemia AML susceptibility in A Moroccan adult population: A case-control study and meta-analysis.

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.

Single nucleotide polymorphisms of multidrug resistance gene 1 (MDR1) and risk of chronic myeloid leukemia.

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.