The impact of IDH and NAT2 gene polymorphisms in acute myeloid leukemia risk and overall survival in an Arab population: A case-control study

PLOS ONE RESEARCH ARTICLE The impact of IDH and NAT2 gene polymorphisms in acute myeloid leukemia risk and overall survival in an Arab population: A case-control study Sohaib M. Al-Khatib ID1☯*, Obada Ababneh ID2☯, Hassann Abushukair ID2☯, Nour Abdo3‡, Laith N. Al-Eitan ID4‡ a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Al-Khatib SM, Ababneh O, Abushukair H, Abdo N, Al-Eitan LN (2023) The impact of IDH and NAT2 gene polymorphisms in acute myeloid leukemia risk and overall survival in an Arab population: A case-control study. PLoS ONE 18(7): e0289014. https://doi.org/10.1371/journal. pone.0289014 Editor: Alvaro Galli, CNR, ITALY Received: May 9, 2023 Accepted: July 8, 2023 Published: July 21, 2023 Copyright: © 2023 Al-Khatib et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files. 1 Department of Pathology and Laboratory Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan, 2 Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan, 3 Department of Public Health, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan, 4 Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid, Jordan ☯ These authors contributed equally to this work. ‡ NA and LNAE also contributed equally to this work. * Abstract Acute myeloid leukemia (AML) is a malignancy of the myeloid cells due to the clonal and malignant proliferation of blast cells. The etiology of AML is complex and involves environmental and genetic factors. Such genetic aberrations include FLT3, DNMT3, IDH1, IDH2, NAT2, and WT. In this study, we analyzed the relationship between five, not previously studied in any Arab population, single nucleotide polymorphisms (SNPs) and the risk and overall survival of AML in Jordanian patients. The SNPs are NAT2 (rs1799930 and rs1799931), IDH1 (rs121913500), and IDH2 (rs121913502 and rs1057519736). A total number of 30 AML patients and 225 healthy controls were included in this study. Females comprised 50% (n = 15) and 65.3% (n = 147) of patients and controls, respectively. For AML patients (case group) Genomic DNA was extracted from formalin-fixed paraffin-embedded tissues and from peripheral blood samples for the control subjects group. Genotyping of the genetic polymorphisms was conducted using a sequencing protocol. Our study indicates that NAT2 rs1799930 SNP had a statistically significant difference in genotype frequency between cases and controls (p = 0.023) while IDH mutations did not correlate with the risk and survival of AML in the Jordanian population. These results were also similar in the TCGA-LAML cohorts with the notable exception of the rare NAT2 mutation. A larger cohort study is needed to further investigate our results. Funding: The study was supported by the Jordan University of Science and Technology Grant number 20170174. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Introduction Competing interests: The authors have declared that no competing interests exist. Acute myeloid leukemia (AML) is a malignancy of the myeloid cells due to the clonal and malignant proliferation of blast cells [1]. AML is the most prevalent type of acute leukemia in PLOS ONE | https://doi.org/10.1371/journal.pone.0289014 July 21, 2023 1 / 11 PLOS ONE IDH and NAT2 in acute myeloid leukemia adults with a median age of 68 years. According to Globocan report, the 5-year prevalence of leukemia is 15.26 per 100000 in Jordan in 2020 [2]. The etiology of AML is complex and involves environmental and genetic factors [3]. Such environmental factors include radiation, smoking, obesity, and previous exposure to chemotherapy or radiation; and genetic aberrations include FLT3, DNMT3, IDH1, IDH2, NAT2, and WT1 [4, 5]. As a result, research into somatic mutations and single-nucleotide polymorphisms (SNPs) has aided in gaining a better understanding of the mechanisms driving leukemogenesis, treatment response and improving patients’ survival [6]. N-acetyltransferase 2 (NAT2) is a gene located in the short arm of chromosome 8 and plays a key role in metabolizing carcinogens such as aromatic amines, arylamines and hydrazines throughout acetylation reactions [7]. Such compounds are also found in cigarette smoke [8]. Different SNPs of NAT-2 have been identified which mark up to distinct populations, slow and rapid acetylator [9]. NAT*4 is the wild type form and considered the main example of rapid acetylator while the absence of it with the presence of the other alleles like rs1799930 and rs1799931 denotes a slow acetylator [10]. These variations have been discussed in light of autoimmunity, tuberculosis treatment, Parkinson’s disease, and cancer [11–13]. Previous studies have shown a link between NAT2 slow acetylation phenotype and bladder, lung, colon, breast, liver, and gastric cancers [14–17]. Although some studies showed an association of NAT2 with increased risk and drug response in terms of AML, the results are conflicting with some studies showing these phenotypes did not affect AML risk [18–20]. Isocitrate dehydrogenases (IDH 1 and IDH2) are part of the tricarboxylic cycle and catalyze the reversible reaction between iso-citrate and α-ketoglutarate. IDH mutations have been heavily studied in brain gliomas [21]. It has been found that IDH mutations are closely related to the occurrence and prognosis of glioma [21]. Recently, the role of IDH mutations has been also investigated in AML. The incidence of IDH1 and IDH2 mutations have been associated with leukemogenesis with an incidence ranging from 8% to 12% [22]. These mutations have been associated with leukemogenesis by preventing the revisable reaction of isocitrate to alpha-ketoglutarate in the tricarboxylic acid cycle and, instead, lead to increased production of the oncogenic 2-hydroxyglutarate from alpha-ketoglutarate [23]. However, there is a conflicting evidence about IDH1/2 mutations’ predictive effect on AML [24]. The aim of this study was, therefore, to analyze the relationship between five, not previously studied in any Arab population, single nucleotide polymorphisms (SNPs) and the risk and overall survival of AML in Jordanian Arab patients. The SNPs are NAT2 (rs1799930 and rs1799931), IDH1 (rs121913500), and IDH2 (rs121913502 and rs1057519736). In addition, we wanted to explore the value of these genes in publicly curated data at the multi-omics level. Methods and materials Patients and data collection Paraffin-embedded samples from AML patients (n = 30) were retr (...truncated)