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

Abstract

Background: Acute 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.

Methods: A 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.

Results: miR-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.

Conclusion: Our 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.

Keywords: Mexican population; acute lymphoblastic leukemia; association study; miR-499a; miR-612; mir-146a; mir-196a-2; single nucleotide polymorphism.

Figure 1

Multifactor dimensionality reduction (MDR) analysis. (A) Four-locus MDR model. Genotype combinations with high risk (shaded dark grey) and low risk (shaded light grey) for acute lymphoblastic leukemia (ALL) and their distribution in cases (left bar) and controls (right bar). The patterns of high (shaded and low-risk cells, which differ across each of the different multi locus dimension, means that the influence each genotype on the ALL risk is dependent on the genotypes a each of the other three loci. (B) Interaction entropy graph for gene-gene interaction and ALL risk. Graph shows the percent of the entropy in case-control removed by each factor (boxes) and by each pair-wise combination of attributes (lines). Positive value and orange line indicate low degree of synergy and negative values and blue and green lines mean redundancy. Gold line means independency. (C) The dendrogram graphic shows the presence, strength, and nature of epistatic effects. The shorter the line connecting two attributes the stronger the interaction. Strength of interaction goes from left to right (gray line).