Tobacco use causes many different diseases through the effects of toxic chemicals from smoke. However, not all smokers are afflicted by tobacco-related diseases. Whether a smoker is affected by such a disease is influenced by factors such as the intensity (amount smoked per day) and duration (years smoked) of tobacco use, and other risk factors such as age and alcohol use. There is also evidence that genetic variation may be a risk factor that differentially affect the risks of numerous tobacco-caused diseases in smokers.1
A genetic risk factor is a variation or alteration in a person’s DNA that puts them at greater risk of a specific disease. These changes could be inherited or could have arisen during someone’s lifetime due to DNA damage. Most of these variations are sequences changes (often called mutations) within genes. Changes in a gene sequence can lead to harmful changes in proteins and cells. There are over 20,000 genes present in each person’s copy of DNA. While variation in most of these genes does not affect the risk of disease, changes in specific genes put people at greater risk of diseases such as cancer. Tobacco use causes DNA alterations that cause disease.
This section summarises the latest evidence on the genetic changes that influence the risks of disease for smokers. Genetics may also influence tobacco use, increasing the risk for disease, which is described in Section 5.3.1 Genetics.
3.24.1 Genetic variation that changes metabolic activation of carcinogens
The primary causes of cancer are alterations in a person’s DNA. Smoking causes cancer because the toxic chemicals (carcinogens) in smoke lead to DNA alterations that cause cancer. However, pre-existing DNA variation is likely to put some smokers at even greater risk of cancer.
There are at least three known ways in which genetics can influence the risk of cancer in people who smoke. Firstly, DNA alterations can make people more likely to become addicted to smoking, leading them to smoke more heavily, discussed in Section 5.3.1. Secondly, DNA alterations can increase the toxic effects of carcinogens in tobacco smoke. Thirdly, DNA alterations can increase a person’s risk of cancer, regardless of smoking. This section focusses on the risks due to the second mechanism.
DNA alterations can increase the potency of carcinogens by changing how they are modified by the body. Cigarette smoke contains over 7,000 chemicals, of which at least 69 are known carcinogens.1 Carcinogens from smoke that enter the body are usually modified in an attempt to detoxify them. However, this modification process sometimes makes more potent intermediate forms that bind to DNA, forming DNA adducts that cause mutations and cancer.1 2 This is called metabolic activation. The extent of metabolic activation of carcinogens from smoke differs between people. People who have higher metabolic activation are at higher risk of some cancers.
There is a genetic basis controlling metabolic activation of carcinogens by enzymes. The enzymes are produced from genes that are encoded by DNA. People with DNA variations that change the functioning or amount of these enzymes may end up with higher levels of potent carcinogens in their bodies, increasing their risk of cancer caused by smoking. Alternatively, some people may have a reduction in the amount of an enzyme that is necessary for the detoxifying process. A loss of these enzymes can increase the amount of carcinogens present, again increasing the risk of cancer.
Certain chemicals from cigarette smoke, such as polycyclic aromatic hydrocarbons, heterocyclic compounds, N-nitrosamines, aromatic amines, and heterocyclic aromatic amines, require metabolic activation before forming DNA adducts that damage DNA and cause cancer.1 Alterations in the sequence of genes that make the enzymes to modify these carcinogens are predicted to be responsible for some of the variation in smokers’ susceptibility to cancer.
The 2010 report of the US Surgeon General describes genetic alterations that are predicted to change the risk of lung and bladder cancer.1 Two variants of the CYP1A1 have been found that may lead to different carcinogenic effects. This gene is responsible for modifying polycyclic aromatic hydrocarbons from cigarette smoke, which bind to DNA to cause lung cancer. An increased risk for lung cancer has been seen in Japanese and Chinese people with these gene variants.3-6 The CYP2E1 gene is involved in activation of several different carcinogens from tobacco smoke. A variant of this gene has been found that is associated with an increased risk of lung cancer.7 The GSTM1 gene is responsible for detoxifying numerous types of carcinogens. Loss of the protein from this gene occurs in people who have a “GSTM1 null” mutation. Multiple studies show that people with this mutation have a slightly higher risk of lung cancer than those without.8, 9 The GSTM1 null mutation may also be associated with a higher risk of laryngeal cancer,10 gastric cancer11 and of oral cancer in Asian people but not in Caucasians, with a stronger effect for smokers.12 The protein produced from the NAT2 gene plays an important role in the modification of the aromatic amines associated with bladder cancer caused by cigarette smoke.1 Many studies have shown that people carrying specific variants of the NAT2 gene have an increased risk of bladder cancer.1, 13, 14
3.24.2 Tobacco-caused diseases that are influenced by genetics
There are genetic risk factors for many of the diseases caused by smoking – that affect people regardless of whether or not they smoke. People with a family history of these diseases, or who are carrying some gene variations, have a higher risk of specific diseases than those without. These diseases include many cancers, diabetes, cardiovascular diseases and many other conditions.
People may be exposed to some toxic chemicals in tobacco smoke from sources other than tobacco. For instance, acrolein, a toxic chemical in found in cigarette smoke, is also found in fried foods and emissions produced when frying foods.15 Therefore, the genetic variations described above—the variations that change the metabolic activation of these chemicals—may be risk factors for non-smokers too. There are many other types of gene alterations that put people at risk of disease, whether they smoke or not. However, some genetic risk factors have a stronger effect on smokers than non-smokers.
This section describes some of the major diseases caused by smoking for which genetics has been shown to modify the risk specifically for smokers.
3.24.2.1 Cancer
The enzyme produced by the NAT2 gene metabolises aromatic amines as part of a detoxification process. Variants of NAT2 can modify the risk of cancers such as bladder cancer. About half the Caucasian population have variants of NAT2 that slow activity of the NAT2 enzyme. A meta-analysis of 6 studies has shown that NAT2 “slow activity” variants are a risk factor for bladder cancer only in smokers. Smokers with slow activity NAT2 have a 1.74-fold higher odds of bladder cancer than non-smokers with the same genetics.14
Variants of the CYP1A1 gene are over-represented in people with squamous cell carcinoma of the lungs. The majority of people with this cancer are smokers, however, people with CYP1A1 gene variants developed the cancer after smoking fewer cigarettes. A case—control study showed that, for two variants of CYP1A1, if smokers also had a GST1 null mutation, they had remarkably high odds of squamous cell carcinoma at a low dose of smoking: odds ratios of 16.0 and 41.0 for two specific variants of CYP1A1.3 These very high chances of lung cancer for light smokers show the strong risks that are possible from specific gene variants for smokers.
3.24.2.2 Chronic obstructive pulmonary disease (COPD)
Most people who have COPD are smokers, but not all smokers develop COPD. It’s predicted that COPD results from a complex interaction between genetics and environmental risks, such as smoking and air pollution. Family history of COPD is also strong risk factor for COPD, independent of exposure to cigarette smoke.16
The protein product of the HHIP gene has an important role in formation of the lungs during development. A variant of the HHIP gene is more commonly found in people with COPD and lung function decline.17 It has been shown that smokers with this variant have a greater decline in lung function that ex-smokers. This demonstrates a cooperative effect of smoking and genetic risk on the disease course of COPD.17 Similar results were found for the SERPINA1 gene in the Chinese population. A SERPINA1 gene variant significantly increased the risk of COPD for smokers.18
3.24.2.3 Cardiovascular diseases
Smoking is a cause of coronary heart disease but not all smokers develop this condition. There are genetic risk factors that are also thought to contribute to coronary heart disease. A prospective study of middle-aged men has shown that a genetic risk factor increases the risk of coronary heart disease for smokers, but not non-smokers. In this study, smoking men had almost double the risk compared to non-smokers (1.94-fold). Smokers with a specific variant of the APOE gene had a 3.17-fold increased risk, with no increased risk for non-smokers.19 The APOE gene regulates fat and cholesterol metabolism in the blood and in some organs.
High levels of the protein product of the APOB gene are associated with plaque formation and cardiovascular disease. Specific mutations in the APOB gene lead to a higher level of the APOB protein in the blood, increasing the risk of cardiovascular disease. Smokers who have more than one mutation in their APOB gene have an even higher level of APOB protein.20
A variant of the FMO3 gene is associated with increased risk of hypertension (high blood pressure). A significantly increased risk is seen only for smokers, not non-smokers.21
3.24.2.4 Crohn’s disease
Smoking is a risk factor for Crohn’s disease (see Section 3.12.2). A variant of the ATG16L1 gene is predicted to increase susceptibility to Crohn’s disease by 2 to 3-fold. Smokers with this variant had an even higher risk of 7-fold, compared to non-smokers.22 A similar interaction was found for smokers with variants of the IL23R gene.23 Numerous variants in the HLA gene region also appear to modify the risk of Crohn’s disease for smokers.24
3.24.3 Genetic changes that influence tobacco use behaviour
See Chapter 5, Section 5.3.1 Genetics.
Relevant news and research
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References
1. US Department of Health and Human Services. How tobacco smoke causes disease: the biology and behavioral basis for smoking-attributable disease. A report of the US Surgeon General, Atlanta, Georgia: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010. Available from: https://www.ncbi.nlm.nih.gov/books/NBK53017/.
2. US Department of Health and Human Services. The health consequences of smoking - 50 years of progress. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. Available from: https://www.ncbi.nlm.nih.gov/books/NBK179276/.
3. Nakachi K, Imai K, Hayashi S, and Kawajiri K. Polymorphisms of the CYP1A1 and glutathione S-transferase genes associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese population. Cancer Research, 1993; 53(13):2994-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8319207
4. Nakachi K, Imai K, Hayashi S, Watanabe J, and Kawajiri K. Genetic susceptibility to squamous cell carcinoma of the lung in relation to cigarette smoking dose. Cancer Research, 1991; 51(19):5177-80. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1655248
5. Okada T, Kawashima K, Fukushi S, Minakuchi T, and Nishimura S. Association between a cytochrome P450 CYPIA1 genotype and incidence of lung cancer. Pharmacogenetics, 1994; 4(6):333-40. Available from: https://www.ncbi.nlm.nih.gov/pubmed/7704039
6. Yang XR, Wacholder S, Xu Z, Dean M, Clark V, et al. CYP1A1 and GSTM1 polymorphisms in relation to lung cancer risk in Chinese women. Cancer Letters, 2004; 214(2):197-204. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15363546
7. Le Marchand L, Sivaraman L, Pierce L, Seifried A, Lum A, et al. Associations of CYP1A1, GSTM1, and CYP2E1 polymorphisms with lung cancer suggest cell type specificities to tobacco carcinogens. Cancer Research, 1998; 58(21):4858-63. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9809991
8. Benhamou S, Lee WJ, Alexandrie AK, Boffetta P, Bouchardy C, et al. Meta- and pooled analyses of the effects of glutathione S-transferase M1 polymorphisms and smoking on lung cancer risk. Carcinogenesis, 2002; 23(8):1343-50. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12151353
9. McWilliams JE, Sanderson BJ, Harris EL, Richert-Boe KE, and Henner WD. Glutathione S-transferase M1 (GSTM1) deficiency and lung cancer risk. Cancer Epidemiology, Biomarkers and Prevention, 1995; 4(6):589-94. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8547824
10. Sanchez-Siles M, Pelegrin-Hernandez JP, Hellin-Meseguer D, Guerrero-Sanchez Y, Corno-Caparros A, et al. Genotype of null polymorphisms in genes GSTM1, GSTT1, CYP1A1, and CYP1A1*2A (rs4646903 T>C)/CYP1A1*2C (rs1048943 A>G) in patients with larynx cancer in southeast Spain. Cancers (Basel), 2020; 12(9). Available from: https://www.ncbi.nlm.nih.gov/pubmed/32882964
11. Zhao Y, Deng X, Song G, Qin S, and Liu Z. The GSTM1 null genotype increased risk of gastric cancer: a meta-analysis based on 46 studies. PLoS ONE, 2013; 8(11):e81403. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24244742
12. Zhang ZJ, Hao K, Shi R, Zhao G, Jiang GX, et al. Glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null polymorphisms, smoking, and their interaction in oral cancer: a HuGE review and meta-analysis. American Journal of Epidemiology, 2011; 173(8):847-57. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21436184
13. Marcus PM, Vineis P, and Rothman N. NAT2 slow acetylation and bladder cancer risk: a meta-analysis of 22 case-control studies conducted in the general population. Pharmacogenetics, 2000; 10(2):115-22. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10761999
14. Vineis P, Marinelli D, Autrup H, Brockmoller J, Cascorbi I, et al. Current smoking, occupation, N-acetyltransferase-2 and bladder cancer: a pooled analysis of genotype-based studies. Cancer Epidemiology, Biomarkers and Prevention, 2001; 10(12):1249-52. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11751441
15. Osorio VM and de Lourdes Cardeal Z. Determination of acrolein in french fries by solid-phase microextraction gas chromatography and mass spectrometry. Journal of Chromatography A, 2011; 1218(21):3332-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21168848
16. Hersh CP, Hokanson JE, Lynch DA, Washko GR, Make BJ, et al. Family history is a risk factor for COPD. Chest, 2011; 140(2):343-50. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21310839
17. Zhao J, Li M, Chen J, Wu X, Ning Q, et al. Smoking status and gene susceptibility play important roles in the development of chronic obstructive pulmonary disease and lung function decline: A population-based prospective study. Medicine, 2017; 96(25):e7283. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28640141
18. Deng X, Yuan CH, and Chang. Interactions between single nucleotide polymorphism of SERPINA1 gene and smoking in association with COPD: a case-control study. International Journal of Chronic Obstructive Pulmonary Disease, 2017; 12:259-65. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28138235
19. Humphries SE, Talmud PJ, Hawe E, Bolla M, Day IN, et al. Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study. Lancet, 2001; 358(9276):115-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11463413
20. Roy N, Gaudet D, Tremblay G, and Brisson D. Association of common gene-smoking interactions with elevated plasma apolipoprotein B concentration. Lipids in Health and Disease, 2020; 19(1):98. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32430061
21. Bushueva O, Solodilova M, Churnosov M, Ivanov V, and Polonikov A. The flavin-containing monooxygenase 3 gene and essential hypertension: The joint effect of polymorphism E158K and cigarette smoking on disease susceptibility. International Journal of Hypertension, 2014; 2014:712169. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25243081
22. Fowler EV, Doecke J, Simms LA, Zhao ZZ, Webb PM, et al. ATG16L1 T300A shows strong associations with disease subgroups in a large Australian IBD population: further support for significant disease heterogeneity. American Journal of Gastroenterology, 2008; 103(10):2519-26. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18671817
23. Doecke JD, Simms LA, Zhao ZZ, Roberts RL, Fowler EV, et al. Smoking behaviour modifies IL23r-associated disease risk in patients with Crohn's disease. Journal of Gastroenterology and Hepatology, 2015; 30(2):299-307. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24989722
24. Yadav P, Ellinghaus D, Remy G, Freitag-Wolf S, Cesaro A, et al. Genetic factors interact with tobacco smoke to modify risk for inflammatory bowel disease in humans and mice. Gastroenterology, 2017; 153(2):550-65. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28506689