Polymorphisms in microRNA target sites modulate risk of lymphoblastic and myeloid leukemias and affect microRNA binding

Abstract

BackgroundMicroRNA dysregulation is a common event in leukemia. Polymorphisms in microRNA-binding sites (miRSNPs) in target genes may alter the strength of microRNA interaction with target transcripts thereby affecting protein levels. In this study we aimed at identifying miRSNPs associated with leukemia risk and assessing impact of these miRSNPs on miRNA binding to target transcripts.MethodsWe analyzed with specialized algorithms the 3′ untranslated regions of 137 leukemia-associated genes and identified 111 putative miRSNPs, of which 10 were chosen for further investigation. We genotyped patients with acute myeloid leukemia (AML, n = 87), chronic myeloid leukemia (CML, n = 140), childhood acute lymphoblastic leukemia (ALL, n = 101) and healthy controls (n = 471). Association between SNPs and leukemia risk was calculated by estimating odds ratios in the multivariate logistic regression analysis. For miRSNPs that were associated with leukemia risk we performed luciferase reporter assays to examine whether they influence miRNA binding.ResultsHere we show that variant alleles of TLX1_rs2742038 and ETV6_rs1573613 were associated with increased risk of childhood ALL (OR (95% CI) = 3.97 (1.43-11.02) and 1.9 (1.16-3.11), respectively), while PML_rs9479 was associated with decreased ALL risk (OR = 0.55 (0.36-0.86). In adult myeloid leukemias we found significant associations between the variant allele of PML_rs9479 and decreased AML risk (OR = 0.61 (0.38-0.97), and between variant alleles of IRF8_ rs10514611 and ARHGAP26_rs187729 and increased CML risk (OR = 2.4 (1.12-5.15) and 1.63 (1.07-2.47), respectively). Moreover, we observed a significant trend for an increasing ALL and CML risk with the growing number of risk genotypes with OR = 13.91 (4.38-44.11) for carriers of ≥3 risk genotypes in ALL and OR = 4.9 (1.27-18.85) for carriers of 2 risk genotypes in CML. Luciferase reporter assays revealed that the C allele of ARHGAP26_rs187729 creates an illegitimate binding site for miR-18a-3p, while the A allele of PML_rs9479 enhances binding of miR-510-5p and the C allele of ETV6_rs1573613 weakens binding of miR-34c-5p and miR-449b-5p.ConclusionsOur study implicates that microRNA-binding site polymorphisms modulate leukemia risk by interfering with the miRNA-mediated regulation. Our findings underscore the significance of variability in 3′ untranslated regions in leukemia.

Association study of the miRNA-binding site polymorphisms of CDKN2A/B genes with gestational diabetes mellitus susceptibility

“…As described above, lower levels of p15 INK4b may relieve the inhibition of CDK6, which facilitates pancreatic b-cell proliferation and thus may lower the risk of diabetes. Nevertheless, we observed that the C allele of rs1063192 was associated with increased risk of GDM, consistent with findings of previous studies [30]. We hypothesize that miR-323b-5p may also regulate other genes crucial for b-cell hyperplasia and insulin signaling and that the SNP rs1063192 influences the functions of other underlying regulation factors in the 3 0 UTR of CDKN2B gene.…”

Regulation of MET-mediated proliferation of thyroid carcinoma cells by miR-449b

“…MiR-449 is a member of the miRNA family and has three different isoforms: a, b, and c. These miR-449s shared a cohort of target genes that belong to the E2F transcription factor-retinoblastoma protein pathway [22,23]. Among all miR-449s, miR-449b has been relatively less studied, although its misexpression has been shown in some types of cancer, including bladder cancer [24], colon cancer [25], leukemia [26], endometrial carcinoma [27], and prostate cancer [28].…”

MicroRNA polymorphisms as markers of risk, prognosis and treatment response in hematological malignancies

“…Although germline polymorphisms are not expected to have a dramatic effect on the cell, as compared to somatic mutations, they may lead to more subtle changes that can gain on significance when several SNPs coexist in a genome. This is illustrated by a trend for a shorter OS in T-cell lymphoma [25] and for a higher risk of ALL and CML [63] with the increasing number of risk genotypes.…”

“…The relevance of SNPs in miRNA-binding sites for various types of leukemia was demonstrated recently [63]. In childhood ALL homozygous carriers of variant alleles of ETV6 rs1573613 and TLX1 rs2742038 had an increased ALL risk, while the variant allele of PML rs9479 was associated with reduced risk of ALL.…”