Table 2.
Predisposition to childhood ALL and miRNA SNPs.
| Study | Cohort Characteristics | Methods | Outcomes |
|---|---|---|---|
| Siyadat et al., 2021 [92] | 100 childhood B-ALL patients and 105 controls; Iran | RT-PCR, HRM and Sanger sequencing; BM or whole blood | No significant relationship was confirmed between rs12803915 variants of miR-612 and susceptibility to B-ALL. |
| Pei et al., 2020 [90] | 266 childhood ALL patients and 266 controls; Taiwan | PCR-RFLP; whole blood | The G allele of miR-146a polymorphism rs2910164 seems to be a protective biomarker for childhood ALL (OR, 0.66; 95% CI: 0.52 to 0.85; p = 0.0011), whereas patients with the GG genotype were associated with decreased susceptibility to ALL (OR, 0.4; 95% CI: 0.23 to 0.67; p = 0.0004) compared with healthy controls. Conspicuously, children bearing CG and GG genotypes were found to have earlier onset compared to those with CC genotype (p = 0.025 and p = 0.0001, respectively). The G>C polymorphism leads to reduced amounts of mature miR-146a, whereas the C allele has reduced capacity to inhibit target genes. |
| C.C. Chen et al., 2020 [93] | 266 childhood ALL patients and 266 controls; Taiwan | PCR-RFLP; whole blood | The T>C polymorphism of rs11614913 in miR-196a-2 does not seem to be associated with susceptibility to childhood ALL. |
| De Souza et al., 2020 [88] | 100 childhood B-ALL patients and 180 adult controls; Brazil | qRT-PCR; whole blood | The mutant homozygote (AA) genotype of DROSHA rs3805500 was associated with a threefold increase in the risk of developing ALL (recessive model: GG + GA vs. AA; OR, 2.913; 95% CI: 1.415 to 5.998; p = 0.004). The mutant homozygote (GG) genotype of the miR-499 gene rs3746444 was associated with a 17.8-fold increase in the risk of developing ALL (recessive model: AA + AG vs. GG; 95% CI: 5.55 to 57.016; p < 0.001). In contrast, the wild homozygous (CC) genotype of the miR-938 gene rs2505901 seems to confer a protective effect against developing ALL (dominant model: CC vs. CT + TT; OR, 0.359; 95% CI: 0.160 to 0.805; p = 0.013). No significant associations for AGO1 rs636832, MIR219A1 rs213210 and rs107822, MIR146A rs2910164, MIR330 rs12894467 and MIR608 rs4919510. |
| Jemimah Devanandan et al., 2019 [47] | 71 childhood ALL patients and 74 controls; India | qRT-PCR; whole blood | No statistically significant association was found between miR-146a gene SNPs rs2910164 G>C and rs57095329 A>G and ALL risk. |
| Xue et al., 2019 [42] | 831 childhood ALL patients and 1079 controls; validation: 88 childhood ALL cases and 99 controls; China |
qRT-PCR; whole blood; plasma from validation cohort | Subjects carrying the mutant homozygous TT genotype of miR-100 rs543412 had a statistically significantly decreased risk of childhood ALL (OR, 0.73; 95% CI: 0.55 to 0.97; p = 0.029). No association was been found for miR-146a rs2910164 and miR-210 rs7395206 polymorphisms and ALL. |
| Gutierrez-Camino et al., 2018 [94] | 217 children with B-ALL and 330 controls from Spain and 75 children with B-ALL and 96 controls from Slovenia | GoldenGate genotyping assay and OpenArray genotyping; whole blood or BM |
The AA genotype of rs12402181 in miR-3117-3p was associated with B-ALL risk (OR, 1.44; 95% CI: 1.01 to 2.08; p = 0.047; GG vs. AG vs. AA) in the Spanish cohort. The same effect was observed in the Slovenian cohort (OR, 2.01; 95% CI: 1.02 to 3.95; p = 0.041). When both populations were analyzed together, they displayed a more significant trend (OR, 1.53; 95% CI: 1.12 to 2.09; p = 0.006). With respect to allele frequency analysis, minor allele A showed a 1.51-fold increased risk of B-ALL in total (95% CI: 1.11 to 2.05; p = 0.007). The CT/CC genotype in rs62571442 of miR-3689d-2 was associated with a significantly increased risk of developing B-ALL (OR, 1.48; 95% CI: 1.02 to 2.15; p = 0.039) in the Spanish cohort, whereas the risk was even greater in the Slovenian cohort (OR, 3.57; 95% CI: 1.57 to 8.12; p = 0.001). Analyzed together, both cohorts confirmed the latter association (OR, 1.31; 95% CI: 1.06 to 1.60; p = 0.011). Allele frequency analysis in both populations showed that minor allele C is associated with a 1.31-fold increased risk of B-ALL (95% CI: 1.06 to 1.6; p = 0.012). |
| Liu et al., 2018 [95] | 200 childhood ALL patients and 100 controls; China | RFLP; whole blood | The miR-146a rs2910164 CC or CG genotype significantly increased the risk of ALL (frequency of GG, GC and CC genotypes in the patient group and in the control group was 16%, 44.5%, 39.5%, and 29%, 41%, 30%, respectively). The expression of GC/CC genotypes were significantly higher in patients than in controls (GG genotype as reference; for the GC genotype: OR, 1.967; 95% CI: 1.054 to 3.672; p = 0.037; and for the CC genotype: OR, 2.386; 95%CI: 1.239 to 4.595; p = 0.012). |
| Rakmanee et al., 2017 [96] | 104 childhood ALL patients and 180 controls; Thailand | PCR-RFLP; whole blood | Variant CC of rs11614913 in miR-196a-2 (OR, 4.321; 95% CI: 2.091 to 8.930; p < 0.001), TC heterozygote (OR, 2.248; 95% CI: 1.103 to 4.579; p = 0.024) and CC+TC genotypes (OR, 2.921; 95% CI: 1.504 to 5.673; p = 0.001) were associated with childhood ALL susceptibility compared with the TT wild type. CC homozygotes were associated with significantly increased miR-196a-2 expression. |
| Chansing et al., 2016 [97] | 100 childhood ALL patients and 200 controls; Thailand | PCR-RFLP; whole blood | There was no association between miR-146a rs2910164 G>C polymorphism and susceptibility to childhood ALL. |
| Hashemi et al., 2016 [98] | 110 childhood ALL patients and 120 controls; Iran | PCR-RFLP; whole blood | A study of polymorphism rs4938723 in pri-miR-34b/c in ALL and healthy children revealed decreased risk of ALL in heterozygous (OR, 0.48; 95% CI: 0.28 to 0.84; p = 0.012; TC vs. TT), and overdominant (OR, 0.51; 95% CI: 0.3 to 0.89; p = 0.02; TC vs. TT+CC) inheritance models. The C allele significantly decreased the risk of childhood ALL compared to the T allele (OR, 0.52; 95% CI: 0.33 to 0.83; p = 0.006). |
| Tong et al., 2016 [99] | 570 childhood ALL patients at diagnosis and 673 controls; China | RT-PCR; whole blood | The CC genotype in rs4938723 of pri-miR-34b/c was associated with significantly reduced ALL risk (CC vs. TT: OR, 0.51; 95% CI: 0.33 to 0.8; p = 0.003, and CC vs. TT+TC: OR, 0.49; 95% CI: 0.32 to 0.75; p = 0.002). |
| Gutierrez-Camino et al., 2014 [91] | 213 childhood precursor B-ALL patients and 387 adult controls; Spain | OpenArray; remission BM or whole blood | The A allele of rs12803915 in premature mir-612 was found to be protective (GG vs. GA vs. AA; OR, 0.61; 95% CI: 0.42 to 0.88; p = 0.007) against ALL risk. The G allele of rs3746444 in the seed region of mature miR-499-3p was also found to be protective (AA vs. AG vs. GG; OR, 0.67; 95% CI: 0.49 to 0.91; p = 0.009). An association with rs10061133 in mir-449b was also identified (AA vs. GA+GG; OR, 0.52; 95% CI: 0.31 to 0.89; p = 0.012). Eight SNPs present in the six miRNA biogenesis pathway genes (TNRC6B, DROSHA, DGCR8, EIF2C1 or AGO1, CNOT1 and CNOT6) were also identified. |
| Hasani et al., 2014 [89] | 75 childhood ALL patients and 115 controls; Iran | T-ARMS-PCR; whole blood | The G>C variant of rs2910164 in hsa-miR-146a was found to significantly increase risk of ALL (CC vs. GG; OR, 4.24; 95% CI: 1.52 to 11.87; p = 0.006, and GC vs. GG; OR, 3.55; 95% CI: 1.41 to 8.93; p = 0.007; C vs. G; OR 1.73; 95% CI: 1.13 to 2.67; p = 0.012). No association was found between rs3746444 of miR-499 and ALL risk. |
AGO1 = argonaut RISC component 1; CNOT1/6 = carbon catabolite repression 4 protein-NOT transcription complex subunit 1/6; DGCR8 = DiGeorge syndrome critical region gene 8 Microprocessor complex subunit; HRM = high-resolution melt analysis; RFLP = restriction fragment length polymorphism; T-ARMS = tetra-primer amplification refractory mutation system; TNRC6B = trinucleotide repeat-containing adaptor 6B. MicroRNAs in bold indicate statistically significant results.