Multiple testing for SNP-SNP interactions

Most genetic diseases are complex, i.e. associated to combinations of SNPs rather than individual SNPs. In the last few years, this topic has often been addressed in terms of SNP-SNP interaction patterns given as expressions linked by logical operators. Methods for multiple testing in high-dimensional settings can be applied when many SNPs are considered simultaneously. However, another less well-known multiple testing problem arises within a fixed subset of SNPs when the logic expression is chosen optimally. In this article, we propose a general asymptotic approach for deriving the distribution of the maximally selected chi-square statistic in various situations. We show how this result can be used for testing logic expressions - in particular SNP-SNP interaction patterns - while controlling for multiple comparisons. Simulations show that our method provides multiple testing adjustment when the logic expression is chosen such as to maximize the statistic. Its benefit is demonstrated through an application to a real dataset from a large population-based study considering allergy and asthma in KORA. An implementation of our method is available from the Comprehensive R Archive Network (CRAN) as R package 'SNPmaxsel'

Temporal Changes in Total Serum Immunoglobulin E Levels in East German Children and the Effect of Potential Predictors

Background: Elevated total serum immunoglobulin E (IgE) levels are a prominent feature of allergic and parasitic diseases. An epidemiologic study was conducted in East German children to describe trends in the development of total serum IgE levels and analyze the impact of potential determinants. Methods: The study consisted of three cross-sectional surveys in 1992-1993, 1995-1996 and 1998-1999 and was conducted in three areas of the former German Democratic Republic. In total, 8,051 questionnaires were completed by the parents of children aged 5-14 years, supplying information on allergic symptoms and potential risk factors. A total of 5,918 measurements of total serum IgE and specific IgE to 5 common aeroallergens were available from 4,353 schoolchildren. Generalized estimating equations were applied to data from all children and stratified for atopic and nonatopic children to identify trends and estimate the effect of potential determinants on total IgE. Results: Total serum IgE levels decreased significantly with a linear trend in East German schoolchildren between 1992 and 1999, the effect being stronger in nonatopic children. The following factors were associated with lower total serum IgE levels: female gender, living in a household with fewer than 4 people, no history of helminth infestation, younger age group (5-7 years), no parental allergy and high socioeconomic status. No association was seen for `smoking at home' and close contact to pets. Conclusion: Total serum IgE declined parallel to helminth infestation; however, the latter explained the decrease only in part. Furthermore, total IgE developed in an opposite direction to specific IgE, indicating that it has determinants other than allergic sensitization. Copyright (C) 2011 S. Karger AG, Base

Missing Heritability in the Tails of Quantitative Traits? A Simulation Study on the Impact of Slightly Altered True Genetic Models

Objective: Genome-wide association studies have identified robust associations between single nucleotide polymorphisms and complex traits. As the proportion of phenotypic variance explained is still limited for most of the traits, larger and larger meta-analyses are being conducted to detect additional associations. Here we investigate the impact of the study design and the underlying assumption about the true genetic effect in a bimodal mixture situation on the power to detect associations. Methods: We performed simulations of quantitative phenotypes analysed by standard linear regression and dichotomized case-control data sets from the extremes of the quantitative trait analysed by standard logistic regression. Results: Using linear regression, markers with an effect in the extremes of the traits were almost undetectable, whereas analysing extremes by case-control design had superior power even for much smaller sample sizes. Two real data examples are provided to support our theoretical findings and to explore our mixture and parameter assumption. Conclusions: Our findings support the idea to re-analyse the available meta-analysis data sets to detect new loci in the extremes. Moreover, our investigation offers an explanation for discrepant findings when analysing quantitative traits in the general population and in the extremes. Copyright (C) 2011 S. Karger AG, Base

Air temperature and inflammatory and coagulation responses in men with coronary or pulmonary disease during the winter season

Background and Objective Air temperature changes are associated with increased cardiovascular and respiratory risk, but the roles of inflammatory and coagulation markers are not well understood. We investigated the associations between temperature and several blood markers in patients with coronary heart disease (CHD) and pulmonary disease (PD). Methods Two studies were conducted in Erfurt, Germany, over two successive winters. 578 and 381 repeated blood measurements were collected from 57 CHD and 38 PD patients, respectively. Data on patient characteristics and disease history were gathered at baseline. Meteorological data were collected from existing networks. Associations were analysed using additive mixed models with random patient effects. Effect modification by diabetes status was investigated only in CHD patients, as only two PD patients had diabetes. Results Mean daily air temperature varied between -13 degrees C and 16 degrees C in both study periods. A 10 degrees C decrease in the 5-day temperature average before blood withdrawal led to an increase in platelet counts (% change from the mean: 3.0%, 95% CI 0.6% to 5.5%) and fibrinogen (5.5%, 1.3% to 9.7%), no change in C-reactive protein in PD patients, and a decrease in C-reactive protein in CHD patients. A 2-day delayed increase in factor VII associated with temperature decrease was seen in CHD patients (4.9%; 0.7% to 9.2%), while PD patients showed no effect. `Effects in CHD patients without diabetes' into `Effects on factor VII in CHD patients without diabetes'. Conclusions This study suggests that temperature decrease is associated with change in several blood parameters. The complex interplay of blood markers at low temperature may contribute to the observed association between cold and cardiovascular mortality and morbidity

Gene-Gene Interaction between APOA5 and USF1: Two Candidate Genes for the Metabolic Syndrome

Objective: The metabolic syndrome, a major cluster of risk factors for cardiovascular diseases, shows increasing prevalence worldwide. Several studies have established associations of both apolipoprotein A5 (APOA5) gene variants and upstream stimulatory factor 1 (USF1) gene variants with blood lipid levels and metabolic syndrome. USF1 is a transcription factor for APOA5. Methods: We investigated a possible interaction between these two genes on the risk for the metabolic syndrome, using data from the German population-based KORA survey 4 (1,622 men and women aged 55-74 years). Seven APOA5 single nucleotide polymorphisms (SNPs) were analyzed in combination with six USF1 SNPs, applying logistic regression in an additive model adjusting for age and sex and the definition for metabolic syndrome from the National Cholesterol Education Program's Adult Treatment Panel III (NCEP (AIII)) including medication. Results: The overall prevalence for metabolic syndrome was 41%. Two SNP combinations showed a nominal gene-gene interaction (p values 0.024 and 0.047). The effect of one SNP was modified by the other SNP, with a lower risk for the metabolic syndrome with odds ratios (ORs) between 0.33 (95% CI = 0.13-0.83) and 0.40 (95% CI = 0.15-1.12) when the other SNP was homozygous for the minor allele. Nevertheless, none of the associations remained significant after correction for multiple testing. Conclusion: Thus, there is an indication of an interaction between APOA5 and USF1 on the risk for metabolic syndrome

Association of lung function with declining ambient air pollution.

Recent studies have found a declining prevalence of respiratory infections in East German children, along with a tremendous improvement of air pollution since 1990. The present study evaluates the effects of improved air quality on lung function. Three consecutive cross-sectional surveys of schoolchildren ages 11-14 years from three communities in East Germany were performed in 1992-1993, 1995-1996, and 1998-1999. Lung function tests were available from 2,493 children. The annual mean of total suspended particulates (TSP) declined from 79 to 25 micro g/m(3), whereas levels for sulfur dioxide declined from 113 to 6 micro g/m(3). Mean forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV(1)) of the children increased from 1992-1993 to 1998-1999. The adjusted percent change of the geometric mean of FVC was 4.7% for a 50 micro g/m(3) decrease of TSP (p = 0.043) and 4.9% for a decrement of 100 micro g/m(3) SO(2) (p = 0.029). Effects on FEV(1) were smaller and not statistically significant. Our study indicates that a reduction of air pollution in a short time period may improve children's lung function

Reference values of impulse oscillometric lung function indices in adults of advanced age.

Impulse oscillometry (IOS) is a non-demanding lung function test. Its diagnostic use may be particularly useful in patients of advanced age with physical or mental limitations unable to perform spirometry. Only few reference equations are available for Caucasians, none of them covering the old age. Here, we provide reference equations up to advanced age and compare them with currently available equations. IOS was performed in a population-based sample of 1990 subjects, aged 45-91 years, from KORA cohorts (Augsburg, Germany). From those, 397 never-smoking, lung healthy subjects with normal spirometry were identified and sex-specific quantile regression models with age, height and body weight as predictors for respiratory system impedance, resistance, reactance, and other parameters of IOS applied. Women (n = 243) showed higher resistance values than men (n = 154), while reactance at low frequencies (up to 20 Hz) was lower (p<0.05). A significant age dependency was observed for the difference between resistance values at 5 Hz and 20 Hz (R5-R20), the integrated area of low-frequency reactance (AX), and resonant frequency (Fres) in both sexes whereas reactance at 5 Hz (X5) was age dependent only in females. In the healthy subjects (n = 397), mean differences between observed values and predictions for resistance (5 Hz and 20 Hz) and reactance (5 Hz) ranged between -1% and 5% when using the present model. In contrast, differences based on the currently applied equations (Vogel & Smidt 1994) ranged between -34% and 76%. Regarding our equations the indices were beyond the limits of normal in 8.1% to 18.6% of the entire KORA cohort (n = 1990), and in 0.7% to 9.4% with the currently applied equations. Our study provides up-to-date reference equations for IOS in Caucasians aged 45 to 85 years. We suggest the use of the present equations particularly in advanced age in order to detect airway dysfunction

Long-term air pollution exposure and living close to busy roads are associated with COPD in women

BACKGROUND: Lung function and exacerbations of chronic obstructive pulmonary disease (COPD) have been associated with short-term exposure to air pollution. However, the effect of long-term exposure to particulate matter from industry and traffic on COPD as defined by lung function has not been evaluated so far. Our study was designed to investigate the influence of long-term exposure to air pollution on respiratory symptoms and pulmonary function in 55-year-old women. We especially focused on COPD as defined by GOLD criteria and additionally compared the effects of air pollution on respiratory symptoms by questionnaire data and by lung function measurements. METHODS: In consecutive cross sectional studies conducted between 1985–1994, we investigated 4757 women living in the Rhine-Ruhr Basin of Germany. NO(2 )and PM(10 )exposure was assessed by measurements done in an 8 km grid, and traffic exposure by distance from the residential address to the nearest major road using Geographic Information System data. Lung function was determined and COPD was defined by using the GOLD criteria. Chronic respiratory symptoms and possible confounders were defined by questionnaire data. Linear and logistic regressions, including random effects were used to account for confounding and clustering on city level. RESULTS: The prevalence of COPD (GOLD stages 1–4) was 4.5%. COPD and pulmonary function were strongest affected by PM(10 )and traffic related exposure. A 7 μg/m(3 )increase in five year means of PM(10 )(interquartile range) was associated with a 5.1% (95% CI 2.5%–7.7%) decrease in FEV(1), a 3.7% (95% CI 1.8%–5.5%) decrease in FVC and an odds ratio (OR) of 1.33 (95% CI 1.03–1.72) for COPD. Women living less than 100 m from a busy road also had a significantly decreased lung function and COPD was 1.79 times more likely (95% CI 1.06–3.02) than for those living farther away. Chronic symptoms as based on questionnaire information showed effects in the same direction, but less pronounced. CONCLUSION: Chronic exposure to PM(10), NO(2 )and living near a major road might increase the risk of developing COPD and can have a detrimental effect on lung function

Surgical smoke and ultrafine particles

© 2008 Brüske-Hohlfeld et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Ultrafine particles and platelet activation in patients with coronary heart disease – results from a prospective panel study

BACKGROUND: Epidemiological studies on health effects of air pollution have consistently shown adverse cardiovascular effects. Toxicological studies have provided evidence for thrombogenic effects of particles. A prospective panel study in a susceptible population was conducted in Erfurt, Germany, to study the effects of daily changes in ambient particles on various blood cells and soluble CD40ligand (sCD40L, also known as CD154), a marker for platelet activation that can cause increased coagulation and inflammation. Blood cells and plasma sCD40L levels were repeatedly measured in 57 male patients with coronary heart disease (CHD) during winter 2000/2001. Fixed effects linear regression models were applied, adjusting for trend, weekday and meteorological parameters. Hourly data on ultrafine particles (UFP, number concentration of particles from 0.01 to 0.1 μm), mass concentration of particles less than 10 and 2.5 μm in diameter (PM(10), PM(2.5)), accumulation mode particle counts (AP, 0.1–1.0 μm), elemental and organic carbon, gaseous pollutants and meteorological data were collected at central monitoring sites. RESULTS: An immediate increase in plasma sCD40L was found in association with UFP and AP (% change from geometric mean: 7.1; CI: [0.1, 14.5] and 6.9; CI: [0.5, 13.8], respectively). Platelet counts decreased in association with UFP showing an immediate, a three days delayed (lag 3) and a 5-day average response (% change from the mean: -1.8; CI: [-3.4,-0.2]; -2.4; CI: [-4.5,-0.3] and -2.2; CI: [-4.0,-0.3] respectively). CONCLUSION: The increased plasma sCD40L levels support the hypothesis that higher levels of ambient air pollution lead to an inflammatory response in patients with CHD thus providing a possible explanation for the observed association between air pollution and cardiovascular morbidity and mortality in susceptible parts of the population