Association between DNA Methyltransferases 3B Gene Polymorphisms and the Susceptibility to Acute Myeloid Leukemia in Chinese Han Population

Abstract

DNMT3B plays a crucial role in the generation of aberrant methylation during carcinogenesis. Polymorphisms in the DNMT3B gene may influence the DNA methylation enzymatic activity of DNMT3B, thereby modulating the susceptibility to AML. Thus, we investigated the association between SNPs in the DNMT3Bgene and their haplotypes with the risk of AML in the Chinese Han population. The DNMT3B genotype was determined by HRM in 317 de novo AML patients and 406 healthy control subjects matched for age and gender. Among the 5 SNPs investigated in this study, rs2424913 demonstrated no polymorphisms in the Chinese Han populations, rs1569686 and rs2424908 were significantly associated with AML risk. The GG genotype of rs1569686 was associated with increased AML risk (OR: 5.76; 95%CI: 2.60-12.73; P<0.01) compared with the TT genotype, and individuals with a G allele had a significantly increased risk (OR: 1.89; 95%CI: 1.41-2.52; P<0.01) for AML compared with those harboring a C allele, this polymorphism can predict the risk of AML in a minority of patients. While the CC genotype of rs2424908 appeared to reduce the AML risk (OR: 0.57; 95%CI: 0.36-0.91; P=0.01) compared with the TT genotype, individuals with a C allele were associated with a lower risk (OR: 0.79, 95%CI: 0.64-0.97, P=0.03) for developing AML compared with those harboring a T allele. The other 2 SNPs, rs6087990 and rs6119954, had no significant association with AML risk in the study population. The CGGT, CTAT, TGAT, and CGAT haplotypes of rs6087990, rs1569686, rs6119954, and rs2424908 appeared to significantly increase the AML risk, and the TTGC haplotype appeared to significantly reduce the risk. These results suggest that DNMT3B polymorphisms may contribute to the genetic susceptibility to AML; in particular, the G allele of rs1569686 serves as a risk factor for AML, whereas the C allele of rs2424908 represents a potential protective factor.

Genetic variants involved in oxidative stress, base excision repair, DNA methylation, and folate metabolism pathways influence myeloid neoplasias susceptibility and prognosis

“…In the present study, we observed that DNMT3B T carrier genotypes (CT and TT) may offer a protective effect against AML development, while SLC19A1 G carrier genotypes (AG and GG) increased the risk of this malignancy. Although, the association of DNMT3B variants with cancer susceptibility has been reported in the literature , it remains unclear . To our best knowledge, only one report studied the association of DNMT3B gene with hematological neoplasias , finding that C allele could confer a protective effect against AML development in Chinese Han population.…”

“…Although, the association of DNMT3B variants with cancer susceptibility has been reported in the literature , it remains unclear . To our best knowledge, only one report studied the association of DNMT3B gene with hematological neoplasias , finding that C allele could confer a protective effect against AML development in Chinese Han population. In the present study, we found that DNMT3B TT genotype was associated with lower DNA methylation, which could explain it protective effect against AML development.…”

“…The hypermethylation of tumor suppressor genes and the global DNA hypomethylation had been implicated as major mechanisms involved in AML development . Also, a large number of recurrent genetic abnormalities found in AML patients occur in genes involved in epigenetic modulators, such as TET2 and DNMT3A .…”

A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in a complex disease

“…We therefore confirmed that the identified annotations for SNP regulatory effects are consistent with the available literature. In particular, SNP rs608799 is located -283bp from the exon 1A transcription start site in the DNMT3B promoter region and is a CPG rich area 49 , which has been annotated as a transcription factor binding site and prioritised for IBD previously 50 ; rs11168249 is an intronic SNP (HDAC7) within a known transcription factor binding rich loci, therefore the annotation of the SNP affecting a transcription factor binding site is highly probable. Rs11041476 (affecting LSP1) and rs7404095 (affecting PKCB) are both experimentally validated SNPs affecting miRNA TS 51 .…”

Association of DNMT3B -283T>C polymorphism with risk of lung and gastric cancer: a case-control study and a meta-analysis

“…Recently, -283T>C has been widely studied to explore the association of DNMT3B with the risk of cancer (15,(17)(18)(19)(20)(21). However, the results from previous studies remain conflicting rather than conclusive.…”