12. Gene environmental interaction
12.4. Smoking-genome interaction
The smoking is one of the strongest and well-measurable environmental factors, and there are several genetic and genomic results about its interaction with the genome.
This interaction can be studied in two different aspects. First, it may sound surprising, but smoking can be regarded as a complex, multifactorial disease, similarly to drug abuse and alcoholism. On the other hand, it is well-known that it increases the risk of several diseases, like lung cancer, asthma, COPD, atherosclerosis or Alzheimer-disease.
These diseases do not develop in all smokers, meaning that other factors are necessary for the development of these diseases. The strongest among these factors is the genomic background of the smokers.
12.4.1. Genomic background of smoking
The heritability of smoking is higher than that of several other polygenic diseases, it is 60%.
It is well known that in smokers stress induces cigarette-craving. In a study it was investigated, whether this had a genetic background. Significantly stronger stress-induced cigarette craving was found for individuals carrying either the DRD2 (D2
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dopamine receptor gene) A1, or the SLC6A3 (dopamine transporter gene) nine-repeat allelic variants. Stress-induced craving was markedly higher for those carrying both alleles, compared to those with neither, consistent with the separate biological pathways involved (receptor, transporter). These findings provide strong support for the possibility that the dopamine system is involved in stress-induced craving and suggest a potential genetic risk factor for persistent smoking behavior. This pathway plays also a role in drug abuse or alcoholism. Both allelic variants are associated with lower brain dopaminergic function, and these basal deficits, in turn, are thought to increase the incentive salience of drug use in the presence of triggers (e.g. stress) that might be related to acute phase increases in dopamine levels.
Another important pathway that plays a role in the addiction to smoking is the nicotine pathway. The CYP2A6 gene (19q13.2) codes for an enzyme responsible for the degradation of nicotine. Deficiency of this enzyme is quite common (10-17.6%), and causes reduced degradation of nicotine, and people with this deficiency have reduced possibility of smoking addiction. If they smoke cigarette, they smoke less, and have reduced risk to cancer and emphysema. The nicotine is accumulated in their organisms, their carving will be reduced more quickly, and thus less toxic substance from the smoke will get to their bodies.
Several GWAS were carried out to study the genomic background of smoking. In 2008 three independent GWAS identified a SNP (rs1051730) in a nicotinic receptor subunit gene, which associated with both smoking and lung cancer. There was a discussion, which one is the real association. Then, with the help of association studies it was verified that the genomic region (CHRNA5-CHRNA3-CHRNB4, 15q24; CHRNA = neuronal acetylcholine receptor subunit alpha), where there are several nicotinic receptors was responsible for the association with strong smoking and the link with lung cancer is primarily mediated through the smoking-related phenotypes. When patients with lung cancer were taken out of the population, the association remained.
The significance of the nicotinic receptors was shown by further studies, where additional nicotinic receptor gene cluster (CHRNA6–CHRNB3) on chromosome 8p11 was found to be associated with smoking and also with the quantity of cigarette smoked in a day.
In a Hungarian study a highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed. The 8.1 ancestral haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, the findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking.
12.4.2. Smoking-gene interaction in disease susceptibilities
Previously we have mentioned that smoking in people with alpha 1-antitrypsin deficiency can trigger lung emphysema, COPD and asthma.
The product of the gene GSTM1 glutathione S-transferase plays a role in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione.
Its null mutation is very frequent (39%). This deficiency in smokers is associated with increased risk to asthma and lung cancer. Vitamin C and E can be protective.
Eighty-ninety percent of patients with rheumatoid arthritis (RA) have certain subtypes of HLA-DRB1: DRB1*0401, *0404, *0405, *0408, *0101, *0102, which are called shared epitopes (HLA-(DRB1) SE). Carriers of HLA-SE have an increased susceptibility to RA and this also has a prognostic significance. In RA, smoking is the most important environmental risk factor. In the last years it has been discovered that in RA patients anti-CCP (anti-cyclic citrullinated peptide) auto-antibodies can be detected. In HLA-DRB1 SE carriers smoking can lead to appearance of anti-CCP antibodies. It starts in the lung and years afterwards RA develops. Smoking activates the enzyme peptidylarginine deiminase which catalyzes the conversion of arginine to citrulline in the proteins in the lung. The cigarette smoke functions as local adjuvant, which leads to the production of anti-CCP. The HLA-DRB1-SE variants bind and present citrullinated proteins especially well. Months or years later a mild inflammation in the joints can trigger appearances of citrullinated proteins. In individuals, who have high anti-CCP level it can lead to development of chronic RA. If a smoker is a HLA-SE allele carrier, his/her relative risk is 6.5, in two allele-carriers it is 21.
A gene-gene-environmental interaction can be observed in those who have null mutation in the GSTM1 gene, HLA-SE carriers, and smokers. They have 58-fold risk to development of RA.
The expected life time of smokers is significantly lower than that of non-smokers.
Individuals who are carriers of the C4B*Q0, an inactive variants of the complement C4B gene in the HLA region (6p21.3), have reduced life expectancy. The population frequency of this variant is 16% in young age (below 45), and reduces to 6% in people of 70-79 years of age. These findings were detected in Hungarian populations and confirmed in Icelandic; and showed that carriers of the C4B*Q0 had a substantially increased risk to suffer from myocardial infarction or stroke, and were sorted out from the healthy elderly population. This was associated strongly with smoking both in Iceland and Hungary. The findings indicated that the C4B*Q0 genotype could be considered as a major covariate of smoking in precipitating the risk for acute myocardial infarction and associated deaths.
The CYP1A1 gene belongs to the cytochrome P450 superfamily (CYP). Enzymes in this group catalyze the oxidation of organic substances and they are the main detoxifying agents in the organism. CYP1A1 degrades the toxins in the cigarette smoke. The most frequent cancer in children is the acute lymphoid leukemia (ALL).
Children whose parents are smokers have a significantly higher risk. In a study it was found that if the father smokes at home, then the risk is 1.8-fold. The variations in the CYP1A1 gene alone do not influence the risk to ALL, but if the children are carriers of certain haplotypes of CYP1A1 and their fathers smoke at home, then the risk is 2.8-fold, if the father is a strong smoker, the risk is 4.9-fold.
12.4.3. Smoking-gene interactions in complex diseases
Smoking increases the risk of several complex diseases. Let us see some examples, what genomic backgrounds could influence this risk.
Smoking is a risk factor in asthma. In a whole genome screening a hypothesis was tested, whether inclusion of exposure to environmental tobacco smoke (ETS) would improve the ability to map genes for asthma. 144 white families from the Collaborative Study for the Genetics of Asthma were screened by 323 microsatellites as genetic
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markers, and environmental information about exposure to ETS during infancy was incorporated in the study. Three regions showed a significant increase from the baseline LOD score (chromosome 1p between D1S1669-D1S1665 markers; 5q at D5S1505-D5S816; and 9q at D9S910). The highest LOD score was found on chromosome 5q. In this genomic region 3 candidate genes were found between the markers of D5S1505-D5S816: ADRB2, IL4 and IL13. Among these the strongest candidate is the ADRB2 which codes for the adrenergic β2 receptor, because it is expressed in the lung and binds substances from the cigarette smoke. The receptor has a common variant: Arg16Gly, which influences the amount of expressed receptors, and has pharmacogenetic significance (see in Chapter 13). In another study it was found that compared with never-smoking Gly-16 homozygotes, those ever-smokers who are Arg-16 homozygotes had a significantly increased risk of asthma (odds ratio = 7.81; 95%
confidence interval [CI]: 2.07 to 29.5). This association showed a clear dose-response relationship with the number of cigarettes smoked.
The smoking increases the risk of atherosclerosis and T2DM (type 2 diabetes mellitus) as well. The CYP1A1 gene has a polymorphism called MspI (T6235C). The C allele is associated with a better inducible gene, its frequency is 10%, and it increases the risk to atherosclerosis and T2DM and higher rate of complications only in mild smokers. In heavy smokers the risk of these diseases are so high that the weak effect of this polymorphism could not be detected. This observation suggests that the presence of the rare C allele of the CYP1A1 gene in smokers may enhance predisposition to severe CAD and T2DM.
The variants of the gene APOE (E2, E3, E4) influence the susceptibility to several diseases, like Alzheimer disease, or atherosclerosis. The variants are quite frequent and differ from each other in their reduction potential, and affinity to lipoprotein receptors.
The APOE4 has the lowest reduction potential, meaning that it can reduce least effectively the oxidative stress induced by smoking. In a study the highest levels of oxLDL and risk to atherosclerosis were measured in APOE4 smokers.
Carrying APOE4 is associated with high risk to Alzheimer disease, the same is true for smoking (OR = 4.93) but this risk is the highest in APOE4 smokers (OR = 6.56).