Genetic Polymorphisms as Biomarkers of Susceptibility

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1		Pieranna Chiarella	--	1541	2023-01-18 12:44:59	\|
2	format	Jason Zhu	-2 word(s)	1539	2023-01-19 02:57:36	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijerph20020912

A clean environment is fundamental to human health and well-being. However, environment can be a souce of various stressors, such as bad quality of air, pollution, noise and hazardous substances affecting our health.The human health is also influenced by climate change, producing flood, heatwaves and presence of vector-borne disease affecting the global health. The climate changes, loss of biodiversity loss and land degradation contribute to impact the human well-being. Human health is influenced by various factors; these include genetic inheritance, behavioral lifestyle, socioeconomic and environmental conditions, and public access to care and therapies in case of illness, with the support of the national health system. All these factors represent the starting point for the prevention and promotion of a healthy lifestyle. However, it is not clear to what extent these factors may actually affect the health of an entire population. The exposures to environmental and occupational factors are several, most of which might be poorly known, contributing to influencing the individual health. Personal habits, including diet, smoking, alcohol, and drug consumption, together with unhealthy behaviors, may inevitably lead people to the development of chronic diseases, contributing to increase aging and decrease daily life expectancy. Despite such risks, humans should modify the bad habits in favour of virtuous habits.

health disease lifestyle genetic variability gene polymorphisms environment

1. Introduction

Humans are exposed to a wide variety of environmental and occupational factors throughout their lifespan. These include both naturally occurring toxins and chemical toxicants like pesticides, herbicides, chemicals, and industrial products, most of which have been implicated as possible contributors to human disease susceptibility. In the case of the occupational setting, the dangerous substances are well known and manipulated with strict control, while according to the latest data, it has been estimated that about 24% of all diseases in the world are due to environmental factor exposure. Much of these risks could be avoided through targeted interventions, as confirmed by the World Health Organization report (WHO) entitled “Preventing Disease through healthy environments: towards an estimate of the environmental burden of disease” ^[1]. To give an example, the subjects could be exposed to a mixture of pesticides or a combination of neurotoxic chemical solvents used in several industries such as in transportation, mining, construction, manufacturing, and shipbuilding, whose applications vary from being used individually or in the form of a mixture, such as in glues, paints, and cleaning products. That said, gene polymorphisms have the power to identify susceptible subgroups in exposed populations. However, if a single genetic trait can be associated with an increased risk in specific individuals or populations, these traits should be studied to evaluate the probability of contributing to the risk of developing a disease ^[2].

2. Genetic Polymorphisms and Differences in the Metabolism

Gene polymorphisms contribute to the variability of the human genome. In fact it has been known that genetic variations underlying the phenotipic diversity are known very well, even though there are many other variations that is not known and will be discovered in the next future. There is a relationship between the genetic predisposition of an individual and his or her ability to metabolize a substance. Differences in drug metabolism can lead to severe toxicity or therapeutic failure due to a change in the ratio between the drug dose and the concentration of pharmacologically active substances in the blood as a result of genetic modifications ^[3]. Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups in the population that differ in their ability to perform certain drug biotransformation reactions ^[4]. In general, five distinctive groups of metabolizers have been identified:

(1): The extensive metabolizer (EM) typical of the normal population. These subjects are either homozygous or heterozygous for the wild-type allele and have a normal metabolism;
(2): The slow metabolizer phenotype (SM) that is associated with the accumulation of specific drug substrates in the body, inherited as a recessive autosomal trait due to the mutation or deletion of both alleles showing a slow metabolism. In some patients, the drug is metabolized very slowly, accumulating the substance in the bloodstream;
(3): The poor metabolizers (PM) carry two defective alleles, showing a complete absence of activity. The higher body concentration of the substance may cause adverse effects due to the substance accumulation;
(4): The rapid metabolizers (RM) clear the drug very quickly, and the therapeutic concentration of the drug in the blood and tissues may not be reached. That means the subject should have a higher dose to produce an effect;
(5): The ultra-extensive metabolizer (UEM) is characterized by enhanced drug metabolism due to gene amplification inherited as an autosomal dominant trait. Individuals with the ultra-extensive phenotype are prone to therapeutic failure because the drug concentrations in the plasma at normal doses are by far too low (faster metabolism) ^[5].

3. Metabolism of Drug

Drug metabolism describes the biotransformation of pharmaceutical substances in the body so that they can be eliminated more easily. The majority of metabolic processes involving drugs occur in the liver, as the enzymes that facilitate the reactions are concentrated there. The rate of drug metabolism can vary significantly for different patients. For instance, the CYP2D6 enzyme is responsible for the oxidative metabolism of 20–25% of drugs. The CYP2D6 iso-enzyme is by far the most extensively characterized enzyme from the CYP450 superfamily, which exhibits a polymorphic expression in humans. It accounts for not more than 2.6% of CYP450 in the liver and plays a very important role in the metabolism of almost a hundred of the most commonly used drugs ^[6].

4. Metabolism of Smoke

Tobacco consumption represents the main etiological factor in lung carcinogenesis and lung cancer is the most frequent malignant neoplasm in many countries. Other factors such as individual genetic susceptibility, environmental and occupational exposures, stressful life, poor diet, and many other factors may influence the quality of life of individuals. The European directive on the smoking ban was passed by the European Parliament and Council in 2003. The entry into effect of the EU’s Tobacco Advertising Directive occurred on 31 July 2005 (World Bank Report on the Economics of Tobacco Control, 1999) https://ec.europa.eu/commission/presscorner/dtail/en/IP_05_1013 (accessed on 2 September 2022) ^[7]. In the USA the main cancer-related cause of mortality worldwide in both genders accounts for an estimated 27% of total cancer deaths in 2015 and 20% in the EU in 2016 ^[8]^[9]. Nicotine is the primary psychoactive constituent of tobacco. Despite it is not a carcinogen, this substance is involved in smoking in addition to the continuous exposure to toxic agents present in tobacco smoke. Once inhaled, nicotine enters into the lungs by circulation to bind to nicotinic cholinergic receptors. The dominant pathway of nicotine metabolism in humans is the production of cotinine, which occurs in two steps. Cotinine is a nicotine metabolite used to quantify exposure to active smoke, and especially to passive smoking. The CYP2A6 enzyme is responsible for the majority of nicotine metabolism and is classified into CYP2A6 genotypes with predicted phenotype groups, as described for the CYP2D6 in the above paragraph ^[10].

5. Metabolism of Ethanol

Dependence on alcohol may cause liver disease with a progressive inflammatory process. In particular, alcoholics may undergo hepatic steatosis, a reversible condition resulting in the accumulation of triglycerides in the liver. As a result, the individual may undergo an increase in hepatomegaly. Other negative effects resulting from alcoholism include cardiovascular disease, hypertension, lung inflammation, mood disorders, anxiety, depression, and memory loss ^[11]. The most relevant enzymes of alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) with the contribution of cytochrome P450 (CYP2E1). In general, ethanol is metabolized by alcohol dehydrogenase (ADH) and by aldehyde dehydrogenase (ALDH) enzymes, where acetaldehyde is oxidized to acetate, while CYP2E1 metabolizes a small fraction of the ingested ethanol. The coding variants in both of these genes seem to be protective, decreasing alcoholism risk by increasing local acetaldehyde levels, either because ethanol is oxidized more rapidly or because acetaldehyde is oxidized more slowly. The balance between the rates of ethanol and acetaldehyde oxidation could be crucial in determining acetaldehyde concentrations within cells, such that small differences in the relative activities of ADH and ALDH might produce significant differences in acetaldehyde concentration ^[12]. The distribution of ADH1B and ALDH2 coding variants changes greatly among different populations; for both genes, the most common protective alleles are found in people of East Asian origin ^[13]^[14]. Variations in genes encoding other ADH enzymes influence alcoholism risk in other populations. For example, ADH4 variants strongly affect alcoholism risk in populations of European descent. There are also non-coding variants that may affect the risk of alcoholism ^[12]. Nonetheless, there are many genes unrelated to ethanol metabolism which may affect the risk of being influenced by multiple social and environmental factors. The level of ethanol consumption and the risk of alcoholism mainly depends on the ADH or ALDH alleles. ADH1B and ALDH2 have been reported as the genes most strongly associated with alcoholism risk. A variant of the ADH1B gene (rs1229984, i.e., Arg48His) has been reported to be associated with reduced rates of alcohol and drug dependence. The allele with increased activity and higher oxidation of ethanol to acetaldehyde is His48, encoded by rs1229984. Carriers with one or two ADH alleles, such as (G/A) or (A/A) have a reduced risk of alcoholism, metabolizing alcohol faster than carriers of the G/G genotype ^[15].

References

Prüss-Üstün, A.; Corvalán, C.; WHO. Preventing Disease through Healthy Environments: Towards an Estimate of the Environmental Burden of Disease; WHO: Geneva, Switzerland, 2006; ISBN 92 4 159382 2.
Chiarella, P.; Capone, P.; Carbonari, D.; Sisto, R. A predictive model assessing genetic susceptibility risk at workplace. Int. J. Environ. Res. Public Health 2019, 16, 2012.
Topic, E. The role of pharmacogenetics in management of cardiovascular disease. J. Int. Fed. Clin. Chem. Lab. Med. 2003, 14, 78–88.
Rommel, G.T.; Kim, R.B. Introduction to Clinical Pharmacology. In Clinical and Translational Science, 2nd ed.; Robertson, D., Williams, G., Eds.; Academic Press: Cambridge, MA, USA, 2016; pp. 365–388.
Belle, D.J.; Singh, H. Genetic factors in drug metabolism. Am. Fam. Physician 2008, 77, 1553–1560.
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World Bank. World Bank Report on the Economics of Tobacco Control; World Bank: Washington, DC, USA, 1999.
Tobacco Advertising Ban Takes Effect 31 July. Available online: https://ec.europa.eu/commission/presscorner/detail/en/IP_05_1013 (accessed on 3 July 2022).
Murphy, S.E. Nicotine metabolism and smoking: Ethnic differences in the role of P450 2A6. Chem. Res. Toxicol. 2017, 30, 410–419.
Derby, K.S.; Cuthrell, K.; Caberto, C.; Carmella, S.G.; Franke, A.A.; Hecht, S.S.; Murphy, S.E.; Le Marchand, L. Nicotine metabolism in three ethnic/racial groups with different risks of lung cancer. Cancer Epidemiol. Biomark. Prev. 2008, 17, 3526–3535.
Patel, Y.M.; Park, S.L.; Han, Y.; Wilkens, L.R.; Bickeböller, H.; Rosenberger, A.; Caporaso, N.; Landi, M.T.; Brüske, I.; Risch, A.; et al. Novel association of genetic markers affecting CYP2A6 activity and lung cancer risk. Cancer Res. 2016, 76, 5768–5776.
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Wall, T.; Luczak, S.E.; Hiller-Sturmhofel, S. Biology, Genetics and Environment: Underlying factor influencing alcohol metabolism. Alcohol Res. Curr. Rev. 2016, 38, 59–68.

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Subjects: Public, Environmental & Occupational Health

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Pieranna Chiarella

Pasquale Capone

Renata Sisto

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Update Date: 19 Jan 2023

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