Lack of reproducibility of linkage results in serially measured blood pressure data

BACKGROUND: Using the longitudinal Framingham Heart Study data on blood pressure, we analyzed the reproducibility of linkage measures from serial cross-sectional surveys of a defined population by performing genome-wide model-free linkage analyses to systolic blood pressure (SBP) and history of hypertension (HTN) measured at five separate time points. RESULTS: The heritability of SBP was relatively stable over time, ranging from 11.6 to 23.5% (coefficient of variation = 25.7%). However, the variability in linkage results was much greater. The average correlation in LOD scores at any pair of time points was 0.46 for HTN (NPL All LOD) and 0.17 for SBP (Variance Components LOD). No evidence of reproducible linkage results was found, with a mean κ of 0.02 for linkage to HTN and -0.03 for SBP linkage. At loci with potential evidence for linkage (LOD > 1.0 at one or more time points), the correlation was even lower. The coefficient of variation at loci with potential evidence of linkage was 126% for HTN and 135% for SBP. None of 15 chromosomal regions for HTN and only one of 28 regions for SBP with potential evidence for linkage had a LOD > 1.0 at more than two of the five time points. CONCLUSION: These data suggest that, although heritability estimates at different time points are relatively robust, the reproducibility of linkage results in serial cross-sectional samples of a geographically defined population at successive time points is poor. This may explain in part the difficulty encountered in replicating linkage studies of complex phenotypes

Genome-wide linkage analysis of longitudinal phenotypes using σ(2)(A )random effects (SSARs) fitted by Gibbs sampling

The study of change in intermediate phenotypes over time is important in genetics. In this paper we explore a new approach to phenotype definition in the genetic analysis of longitudinal phenotypes. We utilized data from the longitudinal Framingham Heart Study Family Cohort to investigate the familial aggregation and evidence for linkage to change in systolic blood pressure (SBP) over time. We used Gibbs sampling to derive sigma-squared-A-random-effects (SSARs) for the longitudinal phenotype, and then used these as a new phenotype in subsequent genome-wide linkage analyses. Additive genetic effects (σ(2)(A.time)) were estimated to account for ~9.2% of the variance in the rate of change of SBP with age, while additive genetic effects (σ(2)(A)) were estimated to account for ~43.9% of the variance in SBP at the mean age. The linkage results suggested that one or more major loci regulating change in SBP over time may localize to chromosomes 2, 3, 4, 6, 10, 11, 17, and 19. The results also suggested that one or more major loci regulating level of SBP may localize to chromosomes 3, 8, and 14. Our results support a genetic component to both SBP and change in SBP with age, and are consistent with a complex, multifactorial susceptibility to the development of hypertension. The use of SSARs derived from quantitative traits as input to a conventional linkage analysis appears to be valuable in the linkage analysis of genetically complex traits. We have now demonstrated in this paper the use of SSARs in the context of longitudinal family data

Systematic analysis of different experimental approaches to measure electronic stopping of very slow hydrogen ions

The electronic stopping cross section (SCS) of Ni for slow H+, H2 +, D+ and D2 + ions has been investigated for different types of targets in two complementary experimental geometries, i.e., in transmission and backscattering. To warrant sample purity, both a high purity nickel sheet and nanometer Ni layers were prepared in-situ under ultra-high-vacuum conditions. In an alternative approach, ultra-thin samples were prepared ex-situ as self-supporting foils and as nanometer films on a polished substrate (silicon). Identical SCS results are obtained in backscattering using the in-situ prepared film and the high purity sheet. The ex-situ prepared targets contained considerable concentrations of impurities of low atomic numbers, whose contribution to the SCS can be rectified by applying Bragg's rule using TRIM stopping for the impurities. In this way for the ex-situ targets the accuracy of the resulting SCS data is improved considerably. Concordant stopping cross section data are obtained in both geometries. The achieved accuracy does, however, not permit to spot a possible influence of different impact parameter regimes explored in transmission and in backscattering geometries.Fil: Roth, D.. Johannes Kepler Universitat Linz; AustriaFil: Celedon, C. E.. Universidad Técnica Federico Santa María; Chile. Johannes Kepler Universitat Linz; Austria. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro | Universidad Nacional de Cuyo. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro; ArgentinaFil: Goebl, D.. Johannes Kepler Universitat Linz; AustriaFil: Sánchez, Esteban Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología - Nodo Bariloche | Comisión Nacional de Energía Atómica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología - Nodo Bariloche; Argentina. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro | Universidad Nacional de Cuyo. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro; ArgentinaFil: Bruckner, B.. Johannes Kepler Universitat Linz; AustriaFil: Steinberger, R.. Johannes Kepler Universitat Linz; AustriaFil: Guimpel, Julio Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología - Nodo Bariloche | Comisión Nacional de Energía Atómica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología - Nodo Bariloche; Argentina. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro | Universidad Nacional de Cuyo. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro; ArgentinaFil: Arista, Nestor Ricardo. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro | Universidad Nacional de Cuyo. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro; ArgentinaFil: Bauer, P.. Johannes Kepler Universitat Linz; Austri

Polymorphisms in signal transducer and activator of transcription 3 and lung function in asthma

BACKGROUND: Identifying genetic determinants for lung function is important in providing insight into the pathophysiology of asthma. Signal transducer and activator of transcription 3 is a transcription factor latent in the cytoplasm; the gene (STAT3) is activated by a wide range of cytokines, and may play a role in lung development and asthma pathogenesis. METHODS: We genotyped six single nucleotide polymorphisms (SNPs) in the STAT3 gene in a cohort of 401 Caucasian adult asthmatics. The associations between each SNP and forced expiratory volume in 1 second (FEV(1)), as a percent of predicted, at the baseline exam were tested using multiple linear regression models. Longitudinal analyses involving repeated measures of FEV(1 )were conducted with mixed linear models. Haplotype analyses were conducted using imputed haplotypes. We completed a second association study by genotyping the same six polymorphisms in a cohort of 652 Caucasian children with asthma. RESULTS: We found that three polymorphisms were significantly associated with baseline FEV(1): homozygotes for the minor alleles of each polymorphism had lower FEV(1 )than homozygotes for the major alleles. Moreover, these associations persisted when we performed an analysis on repeated measures of FEV(1 )over 8 weeks. A haplotypic analysis based on the six polymorphisms indicated that two haplotypes were associated with baseline FEV(1). Among the childhood asthmatics, one polymorphism was associated with both baseline FEV(1 )and the repeated measures of FEV(1 )over 4 years. CONCLUSION: Our results indicate that genetic variants in STAT3, independent of asthma treatment, are determinants of FEV(1 )in both adults and children with asthma, and suggest that STAT3 may participate in inflammatory pathways that have an impact on level of lung function

Maternal allergic contact dermatitis causes increased asthma risk in offspring

<p>Abstract</p> <p>Background</p> <p>Offspring of asthmatic mothers have increased risk of developing asthma, based on human epidemiologic data and experimental animal models. The objective of this study was to determine whether maternal allergy at non-pulmonary sites can increase asthma risk in offspring.</p> <p>Methods</p> <p>BALB/c female mice received 2 topical applications of vehicle, dinitrochlorobenzene, or toluene diisocyanate before mating with untreated males. Dinitrochlorobenzene is a skin-sensitizer only and known to induce a Th1 response, while toluene diisocyanate is both a skin and respiratory sensitizer that causes a Th2 response. Both cause allergic contact dermatitis. Offspring underwent an intentionally suboptimal protocol of allergen sensitization and aerosol challenge, followed by evaluation of airway hyperresponsiveness, allergic airway inflammation, and cytokine production. Mothers were tested for allergic airway disease, evidence of dermatitis, cellularity of the draining lymph nodes, and systemic cytokine levels. The role of interleukin-4 was also explored using interleukin-4 deficient mice.</p> <p>Results</p> <p>Offspring of toluene diisocyanate but not dinitrochlorobenzene-treated mothers developed an asthmatic phenotype following allergen sensitization and challenge, seen as increased Penh values, airway inflammation, bronchoalveolar lavage total cell counts and eosinophilia, and Th2 cytokine imbalance in the lung. Toluene diisocyanate treated interleukin-4 deficient mothers were able to transfer asthma risk to offspring. Mothers in both experimental groups developed allergic contact dermatitis, but not allergic airway disease.</p> <p>Conclusion</p> <p>Maternal non-respiratory allergy (Th2-skewed dermatitis caused by toluene diisocyanate) can result in the maternal transmission of asthma risk in mice.</p

Maternal depressive symptoms, maternal asthma, and asthma in school-aged children

BACKGROUND: Little is known about the joint effects of maternal asthma and maternal depression on childhood asthma. OBJECTIVE: To examine whether maternal depression and maternal asthma lead to greater risk of childhood asthma than maternal asthma alone. METHODS: Cross-sectional studies of children (6-14 years old) in San Juan, Puerto Rico (n = 655) and Sweden (n = 6,887) were conducted. In Puerto Rico, maternal depressive symptoms were defined using the Center for Epidemiologic Studies Depression Scale (CES-D) questionnaire. In Sweden, maternal physician-diagnosed depression was derived from national registries, and maternal depressive symptoms were defined using an abbreviated CES-D questionnaire. Childhood asthma was defined as physician-diagnosed asthma plus current wheeze (in Puerto Rico) or plus medication use (in Sweden). Logistic regression was used for multivariable analysis. RESULTS: Compared with Puerto Rican children whose mothers had neither asthma nor depressive symptoms, those whose mothers had asthma but no depressive symptoms had 3.2 times increased odds of asthma (95% confidence interval [CI] = 2.1-4.8) and those whose mothers had asthma and depressive symptoms had 6.5 times increased odds of asthma (95% CI = 3.3-13.0). Similar results were obtained for maternal depression and maternal asthma in the Swedish cohort (odds ratio for maternal asthma without maternal depression = 2.8, 95% CI = 2.1-3.7; odds ratio for maternal asthma and maternal depression = 4.0, 95% CI = 1.7-9.6). Although the estimated effect of maternal asthma on childhood asthma was increased when maternal depressive symptoms (Puerto Rico) or maternal depression (Sweden) was present, there were no statistically significant additive interactions. CONCLUSION: Maternal depression can further increase the risk of asthma in children whose mothers have a history of asthma.National Institutes of Health, HL079966, HL117191, HD052892, HL125666, T32 HD071834Heinz EndowmentsSwedish Research Council through the Swedish Initiative for Research on Microdata in the Social and Medical Sciences, SIMSAM 340-2013-5867Swedish Research Council for Health, Working Life and Welfare (Forte), COFAS Marie Curie FellowshipNIH Eunice Kennedy Shriver National Institute of Child Health & Human Development, T32HD071834, K12HD052892NIH National Heart Lung & Blood Institute, K08HL125666, R01HL117191, R01HL079966Accepte

Chronic virus infections supress atopy but not asthma in a set of children from a large latin american city: a cross-section study

<p>Abstract</p> <p>Background</p> <p>The prevalence of allergic diseases has increased over recent decades in affluent countries, but remains low in rural populations and some non-affluent countries. An explanation for these trends is that increased exposure to infections may provide protection against the development of allergy. In this work we investigated the association between exposure to viral infections in children living in urban Brazil and the prevalence of atopy and asthma.</p> <p>Methods</p> <p>School age children living in poor neighborhoods in the city of Salvador were studied. Data on asthma symptoms and relevant risk factors were obtained by questionnaire. Skin prick tests (SPTs) were performed to seven aeroallergens, and specific IgE was measured to four of these. Viral infections were determined by the presence of specific IgG in serum to Herpes simplex (HSV), Herpes zoster (HZV), Epstein-Barr (EBV), and Hepatitis A (HAV) viruses.</p> <p>Results</p> <p>A total of 644 (49.7%) children had at least one allergen-specific IgE> 0.35 kU/L and 489 (37.7%) had specific IgE> 0.70 kU/L. A total of 391 (30.2%) children were skin test positive (SPT+), and 295 (22.8%) children were asthmatic. The seroprevalence of viral infections was 88.9% for EBV, 55.4% for HSV, 45.5% for VZV and 17.5% for HAV. Negative associations were observed between SPT+ and HSV (OR = 0.64, CI = 0.51, 0.82) and EBV (OR = 0.63, CI = 0.44, 0.89) infections, but no associations were seen between viral infections and the presence of allergen-specific IgE or asthma.</p> <p>Conclusion</p> <p>These data do not support previous data showing a protective effect of HAV against atopy, but did show inverse associations between SPT+ (but not specific IgE+) and infections with HSV and EBV. These findings suggest that different viral infections may protect against SPT+ in different settings and may indicate an immunoregulatory role of such infections on immediate hypersensitivity responses. The data provide no support for a protective effect of viral infections against asthma in this population.</p

Xenobiotic metabolizing enzyme gene polymorphisms predict response to lung volume reduction surgery

<p>Abstract</p> <p>Background</p> <p>In the National Emphysema Treatment Trial (NETT), marked variability in response to lung volume reduction surgery (LVRS) was observed. We sought to identify genetic differences which may explain some of this variability.</p> <p>Methods</p> <p>In 203 subjects from the NETT Genetics Ancillary Study, four outcome measures were used to define response to LVRS at six months: modified BODE index, post-bronchodilator FEV₁, maximum work achieved on a cardiopulmonary exercise test, and University of California, San Diego shortness of breath questionnaire. Sixty-four single nucleotide polymorphisms (SNPs) were genotyped in five genes previously shown to be associated with chronic obstructive pulmonary disease susceptibility, exercise capacity, or emphysema distribution.</p> <p>Results</p> <p>A SNP upstream from glutathione S-transferase pi (<it>GSTP1</it>; p = 0.003) and a coding SNP in microsomal epoxide hydrolase (<it>EPHX1</it>; p = 0.02) were each associated with change in BODE score. These effects appeared to be strongest in patients in the non-upper lobe predominant, low exercise subgroup. A promoter SNP in <it>EPHX1 </it>was associated with change in BODE score (p = 0.008), with the strongest effects in patients with upper lobe predominant emphysema and low exercise capacity. One additional SNP in <it>GSTP1 </it>and three additional SNPs in <it>EPHX1 </it>were associated (p < 0.05) with additional LVRS outcomes. None of these SNP effects were seen in 166 patients randomized to medical therapy.</p> <p>Conclusion</p> <p>Genetic variants in <it>GSTP1 </it>and <it>EPHX1</it>, two genes encoding xenobiotic metabolizing enzymes, were predictive of response to LVRS. These polymorphisms may identify patients most likely to benefit from LVRS.</p

Susceptibility to COPD:Differential Proteomic Profiling after Acute Smoking

Cigarette smoking is the main risk factor for COPD (Chronic Obstructive Pulmonary Disease), yet only a subset of smokers develops COPD. Family members of patients with severe early-onset COPD have an increased risk to develop COPD and are therefore defined as "susceptible individuals". Here we perform unbiased analyses of proteomic profiles to assess how "susceptible individuals" differ from age-matched "non-susceptible individuals" in response to cigarette smoking. Epithelial lining fluid (ELF) was collected at baseline and 24 hours after smoking 3 cigarettes in young individuals susceptible or non-susceptible to develop COPD and older subjects with established COPD. Controls at baseline were older healthy smoking and non-smoking individuals. Five samples per group were pooled and analysed by stable isotope labelling (iTRAQ) in duplicate. Six proteins were selected and validated by ELISA or immunohistochemistry. After smoking, 23 proteins increased or decreased in young susceptible individuals, 7 in young non-susceptible individuals, and 13 in COPD in the first experiment; 23 proteins increased or decreased in young susceptible individuals, 32 in young non-susceptible individuals, and 11 in COPD in the second experiment. SerpinB3 and Uteroglobin decreased after acute smoke exposure in young non-susceptible individuals exclusively, whereas Peroxiredoxin I, S100A9, S100A8, ALDH3A1 (Aldehyde dehydrogenase 3A1) decreased both in young susceptible and non-susceptible individuals, changes being significantly different between groups for Uteroglobin with iTRAQ and for Serpin B3 with iTRAQ and ELISA measures. Peroxiredoxin I, SerpinB3 and ALDH3A1 increased in COPD patients after smoking. We conclude that smoking induces a differential protein response in ELF of susceptible and non-susceptible young individuals, which differs from patients with established COPD. This is the first study applying unbiased proteomic profiling to unravel the underlying mechanisms that induce COPD. Our data suggest that SerpinB3 and Uteroglobin could be interesting proteins in understanding the processes leading to COPD