Association between tobacco substance usage and a missense mutation in the tumor suppressor gene P53 in the Saudi Arabian population

PLOS ONE RESEARCH ARTICLE Association between tobacco substance usage and a missense mutation in the tumor suppressor gene P53 in the Saudi Arabian population Mikhlid H. Almutairi ID1☯*, Bader O. Almutairi1☯, Turki M. Alrubie2, Sultan N. Alharbi3, Narasimha R. Parine4, Abdulwahed F. Alrefaei ID1, Ibrahim Aldeailej5, Abdullah Alamri4, Abdelhabib Semlali6* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia, 2 Master’s Student, Zoology Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia, 3 National Center for Stem Cell Technology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, 4 Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia, 5 Ministry of Health, Riyadh Regional Lab Director, Riyadh, Kingdom of Saudi Arabia, 6 Groupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire, Université Laval, Québec, Canada ☯ These authors contributed equally to this work. * (MHA); (AS) OPEN ACCESS Citation: Almutairi MH, Almutairi BO, Alrubie TM, Alharbi SN, Parine NR, Alrefaei AF, et al. (2021) Association between tobacco substance usage and a missense mutation in the tumor suppressor gene P53 in the Saudi Arabian population. PLoS ONE 16(1): e0245133. https://doi.org/10.1371/journal. pone.0245133 Editor: Alvaro Galli, CNR, ITALY Received: September 8, 2020 Accepted: December 23, 2020 Published: January 22, 2021 Copyright: © 2021 Almutairi 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. Funding: The authors extend their appreciation to the Researchers Supporting Project number (RSP2020/191), King Saud University, Riyadh, Saudi Arabia. Abstract The tumor suppressor gene TP53 and its downstream genes P21 and MDM2 play crucial roles in combating DNA damage at the G1/S cell cycle checkpoint. Polymorphisms in these genes can lead to the development of various diseases. This study was conducted to examine a potential association between tobacco substance usage (TSU) and single-nucleotide polymorphism (SNP) at the exon regions of the P53, P21, and MDM2 genes by comparing populations of smokers and non-smokers from Saudi Arabia. P53 rs1042522 (C/G), P21 rs1801270 (A/C), and MDM2 rs769412 (A/G) were investigated by genotyping 568 blood specimens: 283 from male/female smokers and 285 from male/female non-smokers. The results obtained from the smokers and their control non-smokers were compared according to age, sex, duration of smoking, and type of TSU. Heterozygous CG, homozygous GG, and CG+GG genotypes, as well as the G allele of rs1042522 were significantly associated with TSU in Saudi smokers compared with non-smokers. The C allele frequency of rs1801270 was also associated with TSU in smokers (OR = 1.33, p = 0.049) in comparison with non-smokers, in younger smokers (�29 years) (OR = 1.556, p = 0.03280) in comparison with non-smokers of the same age, in smokers who had smoked cigarettes for seven years or less (OR = 1.596, p = 0.00882), and in smokers who had consumed shisha (OR = 1.608, p = 0.04104) in comparison with the controls. However, the genotypic and allelic frequencies for rs769412 did not show significant associations with TSU in Saudis. The selected SNP of P53 was strongly associated with TSU and may be linked to TSU-induced diseases in the Saudi Arabian population. Competing interests: The authors have declared that no competing interests exist. PLOS ONE | https://doi.org/10.1371/journal.pone.0245133 January 22, 2021 1 / 25 PLOS ONE Abbreviations: TSU, tobacco substance usage; SNPs, single nucleotide polymorphisms; EDTA, ethylenediaminetetraacetic acid; CI, confidence interval; OR, odds ratio; HWE, Hardy-Weinberg equilibrium (HWE); Pro, Proline; Arg, Arginine; Ser, Serine; Glu, Glutamic Acid.. Smoking effects on polymorphism of a tumor suppressor gene Introduction According to the World Health Organisation, global statistics on trends in tobacco substance usage (TSU) indicate that between the years 2000 and 2025, 1.1 billion youth under the age of 15 have smoked, are smoking, or will smoke (https://punchng.com/1-billion-people-smokeglobally-who-says/) [1]. This large number increases the death toll from TSU among males and females in developed countries by 24% [2]. This number also adds to the 10 million people worldwide who, by the year 2030, will die of diseases related to TSU as well as to the 1 billion who will die of these same causes by the end of the 21st century [3]. Several studies have reported an association between TSU and the formation of tumors in the lungs [4, 5], breasts [6, 7], mouth [8, 9], pancreas [10, 11], colon [12, 13], and kidneys [14, 15]. Associations of TSU with other diseases, including periodontal diseases, cardiovascular diseases [16], and asthma [17], have also been reported. Tobacco is known to contain several hundred different toxic substances (https://www.lung.org/quit-smoking/smoking-facts/whats-in-a-cigarette) that can directly alter genes in cells in the small airways [18] and lungs [19], as well as indirectly cause mutations in genes located in the cells in the bloodstream [20]. Two recent studies have identified the effects of TSU on 599 [21] and 290 genes [19]. This work has shed light on which genes undergo dysregulation of their expression in smokers because of their TSU [19], including cell cycle-related genes in particular [22]. In another study conducted in Ishikawa, Japan, the endometrial adenocarcinoma cells of the participants were treated with components of tobacco [23]. An association was found between TSU and the downregulation of the P16 tumor suppressor protein encoded by the CDKN2A gene that slows down cell division [24]. In addition, a reduction in expression was found to occur in the pathways of the cyclin-dependent kinase inhibitors P21 and P27, with their expression increasing inside the levels of transmission of the cyclins D1 and E. Moreover, previous studies have demonstrated the significant association between TSU and mutations in P53, which cause squamous cell carcinoma in the lungs. TSU has been shown to affect the gene expression of P53 [25] by altering its negative regulator, the MDM2 gene [26], which in turn causes MDM2 upregulation in the lungs of cancer patients who are smokers [27]. Recently, single-nucleotide polymorphisms (SNPs) have also been linked to various diseases, including celiac disease [28], rheumatoid arthritis [29], bipolar disorder [30], and asthma [31, 32], as well as lung [33], gastric [34], ovarian [35], and breast cancers [36]. Other studies (...truncated)