Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis

<p>Abstract</p> <p>Background</p> <p>Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity and genetic variations of such networks.</p> <p>Methods</p> <p>In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic syndrome", which is known to be a heterogeneous and polygenic condition with a clinical endpoint (type 2 diabetes mellitus). In the model presented here, genetic factors were not included and no genetic model is assumed except that genes operate in networks. The impact of stratification of the study population on genetic interaction was demonstrated by analysis of several genes previously associated with the metabolic syndrome and type 2 diabetes mellitus.</p> <p>Results</p> <p>The analysis revealed the existence of 19 distinct subpopulations with a different propensity to develop diabetes mellitus within a large healthy study population. The allocation of subjects into subpopulations was highly accurate with an entropy measure of nearly 0.9. Although very few gene variants were directly associated with metabolic syndrome in the total study sample, almost one third of all possible epistatic interactions were highly significant. In particular, the number of interactions increased after stratifying the study population, suggesting that interactions are masked in heterogenous populations. In addition, the genetic variance increased by an average of 35-fold when analysed in the subpopulations.</p> <p>Conclusion</p> <p>The major conclusions from this study are that the likelihood of detecting true association between genetic variants and complex traits increases tremendously when studied in physiological homogenous subpopulations and on inclusion of epistasis in the analysis, whereas epistasis (i.e. genetic networks) is ubiquitous and should be the basis in modelling any biological process.</p

Health service use among children with and without eczema, asthma, and hay fever

BACKGROUND: Atopic diseases, for example, eczema, asthma, and hay fever, are among the most common chronic diseases of childhood. Knowledge on health service use among children with atopic disease is limited. This study aimed to investigate the total use and costs of health services for children with and without eczema, asthma, and hay fever in a Danish general population. METHODS: We conducted a health survey with four complete birth cohorts from the City of Copenhagen. Individual questionnaire data on eczema, asthma, and hay fever for children aged 3, 6, 11, and 15 years were linked to register information on use and costs of health services and prescribed medication and parental education. In total 9,720 children participated (50.5%). RESULTS: We found increased health service use (number of additional consultations per year [95% confidence interval]) among children with current eczema symptoms (1.77 [1.29–2.26]), current asthma symptoms (2.53 [2.08–2.98]), and current hay fever symptoms (1.21 [0.74–1.67]), compared with children without these symptoms. We also found increased use of prescribed medication and most subtypes of health services. Current asthma symptoms and current eczema symptoms, but not current hay fever symptoms, increased the health service costs with at least €300 per year per child. CONCLUSION: Children with eczema, asthma, and hay fever used health services and prescribed medication more than children without these diseases

Mental health associations with eczema, asthma and hay fever in children:a cross-sectional survey

OBJECTIVE: This study aimed to examine the association of eczema, asthma and hay fever with mental health in a general child population and to assess the influence of parental socioeconomic position on these associations. METHODS: We conducted a cross-sectional health survey of children aged 3, 6, 11 and 15 years in the City of Copenhagen, Denmark. Individual questionnaire data on eczema, asthma, and hay fever and mental health problems assessed using the Strengths and Difficulties Questionnaire (SDQ) was linked to register data on demographics and parental socioeconomic position. 9215 (47.9%) children were included in the analyses. RESULTS: Linear regression analyses showed that children with current eczema symptoms had higher SDQ scores (mean difference, 95% CI) of emotional problems (0.26, 0.12 to 0.39), conduct problems (0.19, 0.09 to 0.29) and hyperactivity problems (0.32, 0.16 to 0.48); children with current asthma symptoms had higher SDQ scores of emotional problems (0.45, 0.32 to 0.58), conduct problems (0.28, 0.18 to 0.38) and hyperactivity problems (0.52, 0.35 to 0.69); and children with current hay fever symptoms had higher SDQ scores of emotional problems (0.57, 0.42 to 0.72), conduct problems (0.22, 0.11 to 0.33), hyperactivity problems (0.44, 0.26 to 0.61) and peer problems (0.14, 0.01 to 0.26), compared with children without current symptoms of the relevant disease. For most associations, parental socioeconomic position did not modify the effect. CONCLUSIONS: Children with eczema, asthma or hay fever had more emotional, conduct and hyperactivity problems, but not peer problems, compared with children without these diseases. Atopic diseases added equally to the burden of mental health problems independent of socioeconomic position

The Association of Alcohol and Alcohol Metabolizing Gene Variants with Diabetes and Coronary Heart Disease Risk Factors in a White Population

BACKGROUND: Epidemiological studies have shown a J- or U-shaped relation between alcohol and type 2 diabetes and coronary heart disease (CHD). The underlying mechanisms are not clear. The aim was to examine the association between alcohol intake and diabetes and intermediate CHD risk factors in relation to selected ADH and ALDH gene variants. METHODOLOGY/PRINCIPAL FINDINGS: Cross-sectional study including 6,405 Northern European men and women aged 30-60 years from the general population of Copenhagen, Denmark. Data were collected with self-administered questionnaires, a physical examination, a 2 hour oral glucose tolerance test, and various blood tests. J shaped associations were observed between alcohol and diabetes, metabolic syndrome (MS), systolic and diastolic blood pressure, triglyceride, total cholesterol, and total homocysteine. Positive associations were observed with insulin sensitivity and HDL cholesterol, and a negative association with insulin release. Only a few of the selected ADH and ALDH gene variants was observed to have an effect. The ADH1c (rs1693482) fast metabolizing CC genotype was associated with an increased risk of impaired glucose tolerance (IGT)/diabetes compared to the CT and TT genotypes. Significant interactions were observed between alcohol and ADH1b (rs1229984) with respect to LDL and between alcohol and ALDH2 (rs886205) with respect to IGT/diabetes. CONCLUSIONS/SIGNIFICANCE: The selected ADH and ALDH gene variants had only minor effects, and did not seem to markedly modify the health effects of alcohol drinking. The observed statistical significant associations would not be significant, if corrected for multiple testing

Genetics of the ceramide/sphingosine-1-phosphate rheostat in blood pressure regulation and hypertension

<p>Abstract</p> <p>Background</p> <p>Several attempts to decipher the genetics of hypertension of unknown causes have been made including large-scale genome-wide association analysis (GWA), but only a few genes have been identified. Unsolved heterogeneity of the regulation of blood pressure and the shortcomings of the prevailing monogenic approach to capture genetic effects in a polygenic condition are the main reasons for the modest results. The level of the blood pressure is the consequence of the genotypic state of the presumably vast network of genes involved in regulating the vascular tonus and hence the blood pressure. Recently it has been suggested that components of the sphingolipid metabolism pathways may be of importance in vascular physiology. The basic metabolic network of sphingolipids has been established, but the influence of genetic variations on the blood pressure is not known. In the approach presented here the impact of genetic variations in the sphingolipid metabolism is elucidated by a two-step procedure. First, the physiological heterogeneity of the blood pressure is resolved by a latent class/structural equation modelling to obtain homogenous subpopulations. Second, the genetic effects of the sphingolipid metabolism with focus on <it>de novo </it>synthesis of ceramide are analysed. The model does not assume a particular genetic model, but assumes that genes operate in networks.</p> <p>Results</p> <p>The stratification of the study population revealed that (at least) 14 distinct subpopulations are present with different propensity to develop hypertension. Main effects of genes in the <it>de novo </it>synthesis of ceramides were rare (0.14% of all possible). However, epistasis was highly significant and prevalent amounting to approximately 70% of all possible two-gene interactions. The phenotypic variance explained by the ceramide synthesis network were substantial in 4 of the subpopulations amounting to more than 50% in the subpopulation in which all subjects were hypertensive. Construction of the network using the epistatic values revealed that only 17% of the interactions detected were in the direct metabolic pathway, the remaining jumping one or more intermediates.</p> <p>Conclusions</p> <p>This study established the components of the ceramide/sphingosine-1-phosphate rheostat as central to blood pressure regulation. The results in addition confirm that epistasis is of paramount importance and is most conspicuous in the regulation of the rheostat network. Finally, it is shown that applying a simple case-control approach with single gene association analysis is bound to fail, short of identifying a few potential genes with small effects.</p

Cross-sectional analysis of sleep hours and quality with sex hormones in men

Background: Reduced total hours of sleep and low quality of sleep have been suggested to be associated with low levels of male hormones. Few studies have examined the association between excessive sleep and male reproductive hormones. Objective: To investigate the association of total hours of sleep and quality of sleep with serum levels of total, bioavailable and free testosterone (tT, bT and fT), sex hormone-binding globulin (SHBG) and dehydroepiandrosteron-sulfate (DHEAS). Methods: Serum levels of tT, SHBG and DHEAS were measured with immunoassays in a cross-sectional population-based study of 2095 males. bT and fT were calculated in accordance with Vermeulens method. Information on total hours of sleep and sleep quality was obtained by questionnaire. Linear regression was used to calculate hormones according to total hours of sleep and the results were expressed as β-estimates and 95% confidence intervals (CI). The adjustment in the multivariable models was constructed taking age, BMI, smoking, alcohol intake and physical activity into account. Results: Excessive sleep (>9 h) compared to 7–9 h of sleep was significantly associated with lower tT, bT and fT, but not with SHBG or DHEAS, after multivariable adjustment. These significant associations were also found in our analyses with hormones as continuous variables but no associations were found in our general additive model analyses. Conclusions: In this cross-sectional study in men, excessive sleep associated with lower levels of male reproductive hormones. Longitudinal studies are needed to determine the causal direction of the observed association between excessive sleep and lower male reproductive hormones levels