miRNA polymorphisms are associated with risk of developing chronic lymphocytic leukemia

Abstract

Chronic Lymphocytic Leukemia (CLL) is the most frequent leukemia of adults in Western countries and shows a ~8.5-fold increased relative risk in first-degree relatives. Up to date several studies have identified low-penetrance susceptibility alleles in CLL. Nevertheless, these studies scarcely study regions that do not encode proteins 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. Polymorphisms in these miRNAs may deregulate miRNAs expression levels and affect to the miRNA function. However, despite accumulating evidence that inherited genetic variation in miRNA genes can contribute to the predisposition for CLL, the role of these in the risk of CLL has not been extensively studied. Therefore, the aim of this study was to find new genetic markers of risk to CLL. To that end, we made a systematic search for SNPs in miRNAs and miRNAs deregulated in CLL and genotyped 213 polymorphisms in 401 samples of Spanish individuals. The literature search resulted in more than 100 miRNAs deregulated in CLL and 43 polymorphisms studied in the disease. Out of 213 genotyped SNPs, 13 showed to be significantly associated with CLL risk. rs2682818 in pre-mature miR618 was the most significant result, with 0.49 fold decreased risk to CLL. Interestingly, a previous study associated this SNP with an increased risk of developing follicular lymphoma. Secondly, rs10173558 SNP in mir- 1302-4 showed the highest risk association, with a 5.24 fold increased risk, but there were no previous works studying it. Finally, rs61992671 in miR412, previously associated with CLL risk, showed also association in our sample. In conclusion, we find 13 alleles which could contribute to the risk of CLL. However, new large-scale studies including functional analyses will be needed to validate our findings.