Genetic Variants in MiRNA Processing Genes and Pre-MiRNAs Are Associated with the Risk of Chronic Lymphocytic Leukemia

<div><p>Genome wide association studies (GWAS) have identified several low-penetrance susceptibility alleles in chronic lymphocytic leukemia (CLL). Nevertheless, these studies scarcely study regions that are implicated in non-coding molecules such as microRNAs (miRNAs). Abnormalities in miRNAs, as altered expression patterns and mutations, have been described in CLL, suggesting their implication in the development of the disease. Genetic variations in miRNAs can affect levels of miRNA expression if present in pre-miRNAs and in miRNA biogenesis genes or alter miRNA function if present in both target mRNA and miRNA sequences. Therefore, the present study aimed to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA processing genes contribute to predisposition for CLL. A total of 91 SNPs in 107 CLL patients and 350 cancer-free controls were successfully analyzed using TaqMan Open Array technology. We found nine statistically significant associations with CLL risk after FDR correction, seven in miRNA processing genes (rs3805500 and rs6877842 in <i>DROSHA</i>, rs1057035 in <i>DICER1</i>, rs17676986 in <i>SND1</i>, rs9611280 in <i>TNRC6B</i>, rs784567 in <i>TRBP</i> and rs11866002 in <i>CNOT1</i>) and two in pre-miRNAs (rs11614913 in miR196a2 and rs2114358 in miR1206). These findings suggest that polymorphisms in genes involved in miRNAs biogenesis pathway as well as in pre-miRNAs contribute to the risk of CLL. Large-scale studies are needed to validate the current findings.</p></div

Significant Haplotypes in miRNA processing genes and Chronic Lymphocytic Leukemia Risk.

<p>^aAdjusted <i>P</i>-value after permutation test</p><p>^bOR values are referred to the rest of haplotype</p><p>Significant Haplotypes in miRNA processing genes and Chronic Lymphocytic Leukemia Risk.</p

Overview of the significant SNPs in the miRNA network.

<p>Overview of the significant SNPs in the miRNA network.</p

Secondary structures of the miRNAs showing significant SNPs.

<p>(A) miR196a2 and (B) miR1206, predicted by the RNAfold tool.</p

Association of significant miRNA-related SNPs and Chronic Lymphocytic Leukemia risk.

<p>Abbreviations: OR, odds ratio; CI, confidence interval; S, significative; NS, no significative</p><p>* Adjusted for multiple comparisons using the False Discovery Rate (FDR) at 5% level</p><p>Association of significant miRNA-related SNPs and Chronic Lymphocytic Leukemia risk.</p