Prevalence of at-risk genotypes for genotoxic effects decreases with age in a randomly selected population in Flanders: a cross sectional study

Abstract

BackgroundWe hypothesized that in Flanders (Belgium), the prevalence of at-risk genotypes for genotoxic effects decreases with age due to morbidity and mortality resulting from chronic diseases. Rather than polymorphisms in single genes, the interaction of multiple genetic polymorphisms in low penetrance genes involved in genotoxic effects might be of relevance.MethodsGenotyping was performed on 399 randomly selected adults (aged 50-65) and on 442 randomly selected adolescents. Based on their involvement in processes relevant to genotoxicity, 28 low penetrance polymorphisms affecting the phenotype in 19 genes were selected (xenobiotic metabolism, oxidative stress defense and DNA repair, respectively 13, 6 and 9 polymorphisms). Polymorphisms which, based on available literature, could not clearly be categorized a priori as leading to an 'increased risk' or a 'protective effect' were excluded.ResultsThe mean number of risk alleles for all investigated polymorphisms was found to be lower in the 'elderly' (17.0 ± 2.9) than the 'adolescent' (17.6 ± 3.1) subpopulation (P = 0.002). These results were not affected by gender nor smoking. The prevalence of a high (> 17 = median) number of risk alleles was less frequent in the 'elderly' (40.6%) than the 'adolescent' (51.4%) subpopulation (P = 0.002). In particular for phase II enzymes, the mean number of risk alleles was lower in the 'elderly' (4.3 ± 1.6 ) than the 'adolescent' age group (4.8 ± 1.9) P < 0.001 and the prevalence of a high (> 4 = median) number of risk alleles was less frequent in the 'elderly' (41.3%) than the adolescent subpopulation (56.3%, P < 0.001). The prevalence of a high (> 8 = median) number of risk alleles for DNA repair enzyme-coding genes was lower in the 'elderly' (37,3%) than the 'adolescent' subpopulation (45.6%, P = 0.017).ConclusionsThese observations are consistent with the hypothesis that, in Flanders, the prevalence of at-risk alleles in genes involved in genotoxic effects decreases with age, suggesting that persons carrying a higher number of at risk alleles (especially in phase II xenobiotic-metabolizing or DNA repair genes) are at a higher risk of morbidity and mortality from chronic diseases. Our findings also suggest that, regarding risk of disease associated with low penetrance polymorphisms, multiple polymorphisms should be taken into account, rather than single ones.

How effective is the European legislation regarding cancer-related chemical agents?

“…A recent report31 by the Danish Environmental Protection Agency concludes that exposure to endocrine disruptors from food, indoor environment and consumer products should be reduced for pregnant women, and that it is important to take the total exposure into account. Furthermore, our vulnerability also seems to be genetically determined 32. As the genetically vulnerable groups are still largely unknown, it is probable that, in addition to those population groups already known to be more vulnerable, other subsets of the population will require extra precautions.…”

Inter-Individual Variability in Xenobiotic-Metabolizing Enzymes: Implications for Human Aging and Longevity

“…In this regard, significant associations of alleles in these genes (especially in phase II genes) with many forms of cancer [12,13] or coronary heart disease [14] were found. Moreover, in testing a sample of individuals of different ages, Ketelslegers et al [15] found that the prevalence of risk alleles in XME genes decreases with age, suggesting that individuals carrying a higher number of risk alleles show a higher risk of morbidity and mortality for chronic diseases.…”

Distinct genotype-dependent differences in transcriptome responses in humans exposed to environmental carcinogens

“…qPCR-based gene expression, biomarkers of cancer risk (micronuclei, COMET assay, 8-hydroxydeoxyguanosine, carcinoembryonic antigen, prostate-specific antigen and p53) and specific cancerrelated SNPs have been measured (16). Subjects were aged 50-65, and were living in the place of residence for more than 5 years.…”

“…Three individuals were left out due to missing genotype data. We used experimental data on exposures to seven compounds (cadmium, lead, marker PCBs, PCB118, p,p′-DDE, HCB, 1-OH-pyrene), and data on 28 cancer risk-associated polymorphisms related to the formation and detoxification of reactive metabolites, to DNA repair and to oxidative stress responses (16). We included the calendar date of the microarray scanning as nuisance variable into the mixed model.…”

“…To combine the individual occurrence of such SNPs into an at-risk profile, genotypes were assigned a specific value depending on the number of risk alleles (16) as follows: Homozygous carriers of 2 alleles with a protective health influence according to literature were coded 0, heterozygous carriers were coded 1 and homozygous carriers of alleles generating an increase in risk were coded 2. Deletions in GSTT1 and in GSTM1 were coded 2, and wild-types 0.…”