Association Analysis Between the Functional Single Nucleotide Variants in miR-146a, miR-196a-2, miR-499a, and miR-612 With Acute Lymphoblastic Leukemia

Abstract

BackgroundAcute lymphoblastic leukemia (ALL) is characterized by an abnormal proliferation of immature lymphocytes, in whose development involves both environmental and genetic factors. It is well known that single nucleotide polymorphisms (SNPs) in coding and noncoding genes contribute to the susceptibility to ALL. This study aims to determine whether SNPs in miR-146a, miR-196a-2, miR-499a, and miR-612 genes are associated with the risk to ALL in pediatric Mexican population.MethodsA multicenter case-control study was carried out including patients with de novo diagnosis of ALL and healthy subjects as control group. The DNA samples were obtained from saliva and peripheral blood, and the genotyping of rs2910164, rs12803915, rs11614913, and rs3746444 was performed using the 5′exonuclease technique. Gene-gene interaction was evaluated by the multifactor dimensionality reduction (MDR) software.ResultsmiR-499a rs3746444 showed significant differences among cases and controls. The rs3746444G allele was found as a risk factor to ALL (OR, 1.6 [95% CI, 1.05–2.5]; p = 0.028). The homozygous GG genotype of rs3746444 confers higher risk to ALL than the AA genotype (OR, 5.3 [95% CI, 1.23–23.4]; p = 0.01). Moreover, GG genotype highly increases the risk to ALL in male group (OR, 17.6 [95% CI, 1.04–298.9]; p = 0.00393). In addition, an association in a gender-dependent manner among SNPs located in miR-146a and miR-196a-2 genes and ALL susceptibility was found.ConclusionOur findings suggest that SNP located in miR-499a, miR-146a, and miR-196a-2 genes confer risk to ALL in Mexican children. Experimental analysis to decipher the role of these SNPs in human hematopoiesis could improve our understanding of the molecular mechanism underlying the development of ALL.

MiRNAs in Hematopoiesis and Acute Lymphoblastic Leukemia

“…The rs3746444G allele was found to be associated with a lower risk for ALL in children of European origin [ 60 ]. Note that, in Brazilians, it was found that the homozygous mutant genotype GG increases the risk of ALL 17-fold [ 81 ], in concordance with the findings described in Mexican children [ 66 ]. However, this polymorphism showed no association with ALL in the Iranian population [ 65 ].…”

“…Recently, an association in a gender-dependent manner among rs2910164G/C and ALL in Mexican children was published. The rs2910164C allele was identified as a risk factor to ALL in males [ 66 ]. However, controversial results have been found in Taiwan by Pei et.…”

“…in the Thai population, and they also reported an association of heterozygote TC genotype, both alone and in combination with CC genotype (TC + CC), increasing the risk of ALL in pediatric patients [ 74 ]. In addition, in Mexican cases, it was observed that the miR-196a rs11614913T allele confers risk to ALL in females [ 66 ]. Conversely, another study from Taiwan showed no association of the rs11614913C/T variant with ALL, thus highlighting the lack of reproducibility even in studies with populations with a similar genetic background [ 75 ].…”