12. Gene environmental interaction
12.5. Examples for gene-environmental interactions
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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).
allele was associated with poor response, while that of the E4 with good response. This implies among others that certain alleles can have both positive and negative effects.
Leukotrienes are inflammatory mediators generated from arachidonic acid by the enzyme 5-lipoxygenase coded by the ALOX5 gene on 10q11.2. Since atherosclerosis involves arterial inflammation, in a study it was investigated whether a repeat polymorphism in the ALOX5 gene promoter could relate to atherosclerosis and that this effect could interact with the dietary intake of competing 5-lipoxygenase substrates. The ALOX5 genotypes, carotid-artery intima-media thickness, and markers of inflammation were determined in a randomly sampled cohort of 470 healthy, middle-aged women and men from the Los Angeles Atherosclerosis Study. Dietary arachidonic acid and marine n-3 fatty acids were measured with the use of six 24-hour recalls of food intake. Variant ALOX5 homozygotes (lacking the common allele) were found in 6.0 percent of the cohort. Mean intima-media thickness adjusted for age, sex, height, and racial or ethnic group was increased among carriers of two variant alleles, as compared with carriers of the common (wild-type) allele. Increased dietary arachidonic acid significantly enhanced the apparent atherogenic effect of genotype, whereas increased dietary intake of n-3 fatty acids blunted the effect. According to this study variant ALOX5 genotypes identify a subpopulation with increased atherosclerosis. The observed diet-gene interactions further suggest that dietary arachidonic acids promote, whereas marine n-3 fatty acids inhibit the leukotriene-mediated inflammation that leads to atherosclerosis in this subpopulation.
High level of homocysteine is associated with CAD (coronary atherosclerotic disease). It contributes to damage of the endothelial wall, proliferation of smooth muscle in the blood vessel, and to the development of atherosclerotic plaques. The enzyme MTHFR (methylenetetrahydrofolate reductase) and the vitamin folic acid are important players in the homocysteine metabolic pathway. A common thermolabile variant of the MTHFR gene, C677T (Ala222Val) was associated with high homocysteine level and increased CAD risk in people with low folate intake. The 677TT genotype was associated with the highest risk, but it could be reduced with folate intake.
These two last examples showed that knowing certain genotypes can be advantageous if the environmental factors (here food) can be easily changed to blunt their harmful effects. It is utilized by most personal genomic DTC companies, where on the basis of the genotypes of the costumers personal advice is given.
CD14 is part of the innate immunity and codes for the lipopolysaccharide receptor with a ligand found on the surface of Gram negative bacteria. With the help of toll like receptor 4 (TLR4), it induces a Th1 immune response against the pathogens. In the SNP -159C/T of the CD14 gene, the rarer T allele increases the level of transcription, and the soluble CD14, and decreases the IgE level. In a French study it was studied whether different environments influenced the effect of this allelic variant on allergic rhinitis. The CD14 -159TT genotype was associated with 2-fold reduced risk to atopy and rhinitis.
Exposure to a farming environment in early life was associated with a similar reduced risk of nasal allergies. When farm exposure and CD14 -159C/T were considered together, the risk of nasal allergies and atopy was the most reduced in the subjects who combined both an early-life exposure to a farming environment and the −159TT genotype (OR = 0.21 meaning ~5-fold risk reduction). This study showed that a gene-by-environment interaction between CD14 -159C/T and gene-by-environmental exposure in childhood may modify the development of atopy. This polymorphism could be considered in interventions studies that use microbial stimuli to reduce sensitization. In a similar study TLR2 and CD14 SNPs were associated with asthma and atopic asthma,
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respectively. In addition, CD14, TLR2, TLR4, and TLR9 SNPs modified associations between country living and asthma.
The CD14 gene is a good example for the observation that the effects of a genotype can be even opposite depending on the environmental factors. An interesting finding was published about Karelian ethnic groups living both in Finland and Russia.
Considering the prevalence of asthma/allergic diseases, an East-West gradient has been consistently confirmed between Western affluent countries and Eastern developing countries, with, e.g. atopic diseases being more prevalent in Western than Eastern Europe. Finnish Karelians (Western environment) have previously been shown to have a higher prevalence of allergic disease than Russian Karelians (Eastern environment).
These two areas are geographically adjacent and are expected to have similar outdoor air pollution. The Karelians were one ethnic group until they were artificially divided by a new Finnish/Russian border during the Second World War, after which changes have occurred mainly on the Russian side of the border with an influx of white Russians.
However, the genetic make-up of the two populations should still be similar and, indeed, any differences can be readily detected as allele distribution differences between the populations on each side of the border. The major differences between Finnish and Russian Karelians therefore are likely to be in the cultural, economic and lifestyle conditions, with which they lived since their separation at the time of the Second World War. The study analysed two asthma/atopy-related genes, CD14 and CC16, which were chosen due to strong evidence of gene by environment interactions.
Opposite effects on asthma-related phenotypes were found for specific alleles of both CD14 -159C/T and CC16 A38G in the Karelian women. Of particular interest was the finding of paradoxical gene by environment responses for several allergy phenotypes. For some of these, itchy rash in particular, the CD14 TT genotype conferred the greatest risk among those in Finland, but the TT genotype was associated with the least risk in Russians. A paradox was also found for CC16 as the AA genotype was associated with the greatest risk of rhinitis and allergic eye symptoms in Finnish subjects, but the least risk for these phenotypes in Russians. Gene by environment interactions have been suggested to explain the inconsistencies in the associations of CD14 -159C/T with atopic phenotypes and an endotoxin switch model has been postulated, in which the CD14 promoter polymorphism changes the threshold, at which environmental endotoxin stimulation leads to a TH2 immune response. Several population-based and family-based studies showed that the CD14 -159C/T polymorphism had an interactive effect with endotoxin exposure on atopic phenotypes.
The T allele of the CD14 -159C/T SNP, with possibly higher expression of CD14, exhibited protective effects on atopy with low exposure to endotoxin, in contrast, being a risk factor with high exposure to endotoxin. Russian Karelians in the Eastern environment may have had higher levels of endotoxin exposure, relative to Finnish Karelians in the Western environment. Indeed, recent studies found that Finnish Karelian children had a lower prevalence of microbial antibodies and less exposure to microbial loads in drinking water, compared with Russian Karelian children. With regard to the endotoxin switch model, Russian women with the T allele of CD14 -159C/T, potentially exposed to higher levels of endotoxin relative to Finnish women, should have an increased risk for atopic phenotypes. However, the study found that in Russian women the T allele was protective against atopic conditions, which is inconsistent with the switch model and indicates the complexity of interactions between environmental exposure to endotoxin and genotypes of CD14 (see in Chapter 9, Hygiene hypothesis).
Besides smoking, alcohol consumption is another strong and measurable environmental factor. The first step of the degradation of alcohol is catalyzed by alcohol dehydrogenases (ADH). Among white populations, variant alleles are common at the ADH3 locus (present in 40 to 50 percent). At the ADH3 locus, the γ1 allele differs from the γ2 allele by two amino acids at positions 271 and 349. Pharmacokinetic studies show a 2.5-fold difference in the maximal velocity of ethanol oxidation between the homodimeric γ1 isoenzyme (associated with a fast rate) and the homodimeric γ2 isoenzyme (associated with a slow rate). This difference is thought to affect the rate of oxidation of blood ethanol, although the ADH3 polymorphism had no apparent effect on blood alcohol levels in a short-term study of high-dose alcohol consumption in humans.
Epidemiologic studies have associated the ADH3 polymorphisms with alcohol-associated diseases, such as alcoholism (γ2γ2), alcohol-related end-organ damage (γ1γ1), and oropharyngeal cancer (γ1γ1). In a large study 14,916 USA male physicians between 40-84 years of age were followed up for 12 years. During this follow-up 396 had myocardial infarction (MI). In those who had ADH3 γ2γ2 genotype and consumed at least 14 gram alcohol/day had 0.14 risk of MI (7.1-fold risk reduction) comparing to those who had γ1γ1 genotype and consumed no alcohol. It corresponds to the J-shaped curve found when the relationship between alcohol use and total mortality were studied. The nadir of the curves based on recent meta-analysis suggested optimal benefit at approximately half a drink per day. Fewer than 4 drinks per day in men and fewer than 2 per day in women appeared to confer benefit. Reductions in cardiovascular death and nonfatal myocardial infarction were also associated with light to moderate alcohol intake.
Although some studies suggested that wine had an advantage over other types of alcoholic beverages, other studies suggested that the type of drink was not important.
Heavy drinking was associated with an increase in mortality, hypertension, alcoholic cardiomyopathy, cancer, and cerebrovascular events, including cerebrovascular haemorrhage. Paradoxically, light-to-moderate alcohol use actually reduced the development of heart failure and did not appear to exacerbate it in most patients who had underlying heart failure. Numerous mechanisms have been proposed to explain the benefit that light-to-moderate alcohol intake has on the heart, including an increase of high-density lipoprotein cholesterol (HDL-C), reduction in plasma viscosity and fibrinogen concentration, increase in fibrinolysis, decrease in platelet aggregation, improvement in endothelial function, reduction of inflammation, and promotion of antioxidant effects. According to the previous findings the effect of alcohol consumption is influenced by genetic background, and ADH3 genotypes have a strong role in it. In this study, participants who drank alcohol, and had γ2γ2 genotype, had higher mean HDL-C level, which is known to be protective against atherosclerosis and related diseases like MI. The antagonistic pleiotropy described in Chapter 9 is also a good example for the gene-environmental interaction.