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<p>Genetic polymorphisms in detoxification enzyme genes may influence individual susceptibility to tobacco-related carcinogens. However, the association between metabolizing gene variants, lung cancer (LC), and waterpipe tobacco (WPT) smoking remains largely unexplored. This study aimed to evaluate the association of the NAT2 rs1801280 (T145C) polymorphism, alone and in combination with GSTT1, GSTM1, and GSTP1 variants, with LC risk in Arab Iraqi male WPT smokers. Previously, we investigated the relationship between phase I and II metabolizing gene polymorphisms and LC risk. In this study, we extended the investigation by evaluating the <i>NAT2</i> rs1801280 (T145C) polymorphism, both independently and in combination with <i>GSTT1</i>/<i>GSTM1</i> (active/null), and <i>GSTP1</i> (rs1695 and rs1138272) polymorphisms. A total of 252 male participants (123 LC patients and 129 controls) were genotyped using tetra-ARMS PCR, multiplex PCR, and RFLP-PCR methods. While no significant overall association was found between <i>NAT2</i> rs1801280 genotypes and LC, stratification by WPT smoking revealed that smokers carrying at least one C allele had a significantly increased LC risk (OR 4.60, 95% CI 2.13–9.94, <i>p</i> &lt; 0.001). Interestingly, even non-smokers with the C allele exhibited a more than two-fold increased risk (OR 2.54, 95% CI 1.01–5.86, <i>p</i> = 0.03). Combined genotype analysis showed that carriers of both <i>NAT2</i> rs1801280 and <i>GSTP1</i> rs1695 variant alleles had a significantly elevated risk (OR 2.14, 95% CI 1.03–4.44, <i>p</i> = 0.04), while no significant interaction was found with <i>GSTM1</i> or <i>GSTT1</i>. Although histological subtype analysis did not reach statistical significance, trends toward increased risk were noted in adenocarcinoma and squamous cell carcinoma. These findings highlight <i>NAT2</i> T145C as a potential genetic marker for LC susceptibility, particularly in WPT smokers.</p>

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Association of NAT2 rs1801280 and GSTs Variants with Lung Cancer Risk Among Charcoal-Heated Shisha Smokers in an Iraqi Population

  • 期刊论文

  • 发表日期：

    2026年4月4日

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  • Bassam K. Kudhair,
  • Karrar S. Zayed,
  • Ali A. Majeed,
  • Yasir Adil Jabbar Alabdali,
  • Noralhuda N. Alabid,
  • Inam J. Lafta

摘要

Genetic polymorphisms in detoxification enzyme genes may influence individual susceptibility to tobacco-related carcinogens. However, the association between metabolizing gene variants, lung cancer (LC), and waterpipe tobacco (WPT) smoking remains largely unexplored. This study aimed to evaluate the association of the NAT2 rs1801280 (T145C) polymorphism, alone and in combination with GSTT1, GSTM1, and GSTP1 variants, with LC risk in Arab Iraqi male WPT smokers. Previously, we investigated the relationship between phase I and II metabolizing gene polymorphisms and LC risk. In this study, we extended the investigation by evaluating the NAT2 rs1801280 (T145C) polymorphism, both independently and in combination with GSTT1/GSTM1 (active/null), and GSTP1 (rs1695 and rs1138272) polymorphisms. A total of 252 male participants (123 LC patients and 129 controls) were genotyped using tetra-ARMS PCR, multiplex PCR, and RFLP-PCR methods. While no significant overall association was found between NAT2 rs1801280 genotypes and LC, stratification by WPT smoking revealed that smokers carrying at least one C allele had a significantly increased LC risk (OR 4.60, 95% CI 2.13–9.94, p < 0.001). Interestingly, even non-smokers with the C allele exhibited a more than two-fold increased risk (OR 2.54, 95% CI 1.01–5.86, p = 0.03). Combined genotype analysis showed that carriers of both NAT2 rs1801280 and GSTP1 rs1695 variant alleles had a significantly elevated risk (OR 2.14, 95% CI 1.03–4.44, p = 0.04), while no significant interaction was found with GSTM1 or GSTT1. Although histological subtype analysis did not reach statistical significance, trends toward increased risk were noted in adenocarcinoma and squamous cell carcinoma. These findings highlight NAT2 T145C as a potential genetic marker for LC susceptibility, particularly in WPT smokers.