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Background: It remains unclear to what extent asthma in adults is linked to allergic rhinitis (AR), gastroesophageal reflux disease (GERD), and acetylsalicylic acid exacerbated respiratory disease (AERD), and how these comorbidities may affect asthma outcomes in the general population. We therefore aimed to assess the prevalence of these major comorbidities among adults with asthma and examine their impact on asthma exacerbations requiring hospital care.
Methods: A total of 22,050 adults 18 years and older were surveyed in the German National Health Telephone Interview Survey (GEDA) 2010 using a highly standardized computer-assisted interview technique. The study population comprised participants with self-reported physician-diagnosed asthma, among which the current (last 12 months) prevalence of AR and GERD-like symptoms (GERS), and life-time prevalence of AERD was estimated. Weighted bivariate analyses and logistic regression models were applied to assess the association of each comorbid condition with the asthma outcome (any self-reported asthma-related hospitalization and/or emergency department (ED) admission in the past year).
Results: Out of 1,136 adults with asthma, 49.6% had GERS and 42.3% had AR within the past 12 months; 14.0% met the criteria of AERD, and 75.7% had at least one out of the three conditions. Overall, the prevalence of at least one exacerbation requiring emergency room or hospital admission within the past year was 9.0%. Exacerbation prevalence was higher among participants with comorbidities than among those without (9.8% vs. 8.2% for GERS; 11.2% vs. 7.6% for AR, and 22.2% vs. 7.0% for AERD), but only differences in association with AERD were statistically significant. A strong association between asthma exacerbation and AERD persisted in multivariable logistic regression analyses adjusting for sex, age group, level of body mass index, smoking status, educational attainment, and duration of asthma: odds ratio (OR) = 4.5, 95% confidence interval (CI) = 2.5-8.2.
Conclusions: Data from this large nation-wide study provide evidence that GERS, AR and AERD are all common comorbidities among adults with asthma. Our data underline the public health and clinical impact of asthma with complicating AERD, contributing considerably to disease-specific hospitalization and/or ED admission in a defined asthma population, and emphasize the importance of its recognition in asthma care.
The ERCC4 protein forms a structure-specific endonuclease involved in the DNA damage response. Different cancer syndromes such as a subtype of Xeroderma pigmentosum, XPF, and recently a subtype of Fanconi Anemia, FA-Q, have been attributed to biallelic ERCC4 gene mutations. To investigate whether monoallelic ERCC4 gene defects play some role in the inherited component of breast cancer susceptibility, we sequenced the whole ERCC4 coding region and flanking untranslated portions in a series of 101 Byelorussian and German breast cancer patients selected for familial disease (set 1, n = 63) or for the presence of the rs1800067 risk haplotype (set 2, n = 38). This study confirmed six known and one novel exonic variants, including four missense substitutions but no truncating mutation. Missense substitution p.R415Q (rs1800067), a previously postulated breast cancer susceptibility allele, was subsequently screened for in a total of 3,698 breast cancer cases and 2,868 controls from Germany, Belarus or Russia. The Gln415 allele appeared protective against breast cancer in the German series, with the strongest effect for ductal histology (OR 0.67; 95%CI 0.49; 0.92; p = 0.003), but this association was not confirmed in the other two series, with the combined analysis yielding an overall Mantel-Haenszel OR of 0.94 (95% CI 0.81; 1.08). There was no significant effect of p.R415Q on breast cancer survival in the German patient series. The other three detected ERCC4 missense mutations included two known rare variants as well as a novel substitution, p.E17V, that we identified on a p.R415Q haplotype background. The p.E17V mutation is predicted to be probably damaging but was present in just one heterozygous patient. We conclude that the contribution of ERCC4/FANCQ coding mutations to hereditary breast cancer in Central and Eastern Europe is likely to be small.
Background: A novel non-invasive asthma prediction tool from the Leicester Cohort, UK, forecasts asthma at age 8 years based on 10 predictors assessed in early childhood, including current respiratory symptoms, eczema, and parental history of asthma.
Objective: We aimed to externally validate the proposed asthma prediction method in a German birth cohort.
Methods: The MAS-90 study (Multicentre Allergy Study) recorded details on allergic diseases prospectively in about yearly follow-up assessments up to age 20 years in a cohort of 1,314 children born 1990. We replicated the scoring method from the Leicester cohort and assessed prediction, performance and discrimination. The primary outcome was defined as the combination of parent-reported wheeze and asthma drugs (both in last 12 months) at age 8. Sensitivity analyses assessed model performance for outcomes related to asthma up to age 20 years. Results: For 140 children parents reported current wheeze or cough at age 3 years. Score distribution and frequencies of later asthma resembled the Leicester cohort: 9% vs. 16% (MAS-90 vs. Leicester) of children at low risk at 3 years had asthma at 8 years, at medium risk 45% vs. 48%. Performance of the asthma prediction tool in the MAS-90 cohort was similar (Brier score 0.22 vs. 0.23) and discrimination slightly better than in the original cohort (area under the curve, AUC 0.83 vs. 0.78). Prediction and discrimination were robust against changes of inclusion criteria, scoring and outcome definitions. The secondary outcome 'physicians' diagnosed asthma at 20 years' showed the highest discrimination (AUC 0.89).
Conclusion: The novel asthma prediction tool from the Leicester cohort, UK, performed well in another population, a German birth cohort, supporting its use and further development as a simple aid to predict asthma risk in clinical settings.
Mechanistic possibilitles responsible for nonlinear shapes of the dose-response relationship in chemical carcinogenesis are discussed. (i) Induction and saturation of enzymatic activation and detoxification processes and of DNA repair affect the relationship between dose and steady-state DNA adduct Ievel; (ii) The fixation of DNA adducts in the form of mutations is accelerated by stimulation of the cell division, for Jnstance due to regenerative hyperplasia at cytotoxic dose Ievels; (iii) The rate of tumor formation results from a superposition of the rates of the individual steps. It can become exponential with dose if more than one step is accelerated by the DNA damage exerted by the genotoxic carcinogen. The strongly sigmoidal shapes often observed for dose-tumor incidence relationships in animal bioassays supports this analysis. A power of four for the dose in the su~linear part of the curve is the maximum observed (formaldehyde). In contrast to animal experiments, epidemiological data ln humans rarely show a slgnificant deviation from linearity. The discrepancy might be explained by the fact that a I arge nu mber of genes contribute to the overall sensitivity of an individual and to the respective heterogeneity within the human population. Mechanistic nonlinearities are flattened out in the presence of genetic and life-style factors which affect the sensitivity for the development of cancer. For a risk assessment, linear extrapolation from the high-dose lncidence to the spontaneaus rate can therefore be approprlate in a heterogeneous population even if the mechanism of action would result in a nonlinear shape of the dose-response curve in a homogeneaus population.