Association of TLR4 Rs4986791 Polymorphism and TLR9 Haplotypes with Acute Myeloid Leukemia Susceptibility: A Case-Control Study of Adult Patients.

Claudia Banescu,Erzsebet Lazar,Adrian P Trifa,Anca S Bojan,Carmen Muntean,Mihaela Iancu,Marcela Candea,Laura Jimbu,George Andrei Crauciuc,Florin Tripon,Alina Boglis

doi:10.3390/jpm12030409

Abstract

Toll-like receptors (TLRs) have an important role in innate immunity, and single nucleotide polymorphisms (SNPs) of TLR genes influence the risk of developing hematological malignancies. We aimed to evaluate the effect of TLR2 (rs5743708), TLR4 (rs11536889, rs4986790, rs4986791), TLR9 (rs187084, rs352140, rs5743836) on AML risk, the relation between investigated SNPs and somatic mutations, clinical features, and the overall survival of adult AML patients. All mentioned SNPs were genotyped in 511 AML cases and 503 healthy controls. DNMT3A (R882), FLT3 (D835, ITD), and NPM1 mutations’ status were investigated in AML patients. TLR4 rs4986791 was associated with an increased risk of AML under the dominant model (OR = 1.61, 95% CI: 1.001–2.59). Variant genotypes of the TLR4 rs4986790 or rs4986791 were associated with the odds of developing AML in the codominant model (OR = 3.14; 95% CI: 1.12–8.84; p = 0.032). The TLR9 rs5743836 variant genotype was associated with the NPM1 mutation (p = 0.002). The investigated SNPs were not associated with the DNMT3A, FLT3 mutations and had no significant contribution to the hazard of death after adjusting for covariates. Our findings suggest that TLR4 rs4986791 is associated with AML susceptibility. The combined variant genotypes of TLR4 rs4986790 and rs4986791 increase AML risk, the TLR9 C-G-A haplotype may represent a promising approach to predict a person’s risk for developing AML.

Highlights

Acute myeloid leukemia (AML), an aggressive malignant hematologic neoplasm with an incidence that is increasing with age, is characterized by complex pathogenicity that arises as a consequence of the accumulation of genetic abnormalities [1]
We evaluated the relation between variant genotypes of the TLR2 rs5743708, TLR4, and TLR9 single nucleotide polymorphism (SNP) with somatic mutations (FLT3, NPM1, DNMT3A) and clinical features and overall survival of AML patients
Taking into account the fact that the presence of the combined variant genotype of TLR4 rs4986790 and TLR4 rs4986791 was significantly associated with increased odds of AML, we found that these two gene polymorphisms may have a combined effect and no modifying effect on AML susceptibility

Summary

Introduction

Acute myeloid leukemia (AML), an aggressive malignant hematologic neoplasm with an incidence that is increasing with age, is characterized by complex pathogenicity that arises as a consequence of the accumulation of genetic abnormalities [1]. Genetic factors play an important role in the occurrence and development of AML and are used in its risk stratification [3,5,6]. The innate immune system plays a main role in the body’s defense mechanisms against infections and cancers, including leukemia. Different reports considered that TLRs have a dual role or “double-edged sword” effect in cancer, the antitumoral effects due to efficient immune responses, and the pro-tumoral effects due to the production of pro-inflammatory cytokines and chemokines, anti-apoptotic molecules, and growth factors that increase tumor cell proliferation, promote invasion and metastasis [8,9]. Previous studies have shown that TLRs are expressed in tumor cells, and are involved in tumorigenesis, tumor growth, and metastasis [10–13]

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