Inference of disease associations with unmeasured genetic variants by combining results from genome-wide association studies with linkage disequilibrium patterns in a reference data set

Results from whole-genome association studies of many common diseases are now available. Increasingly, these are being incorporated into meta-analyses to increase the power to detect weak associations with measured single-nucleotide polymorphisms (SNPs). Imputation of genotypes at unmeasured loci has been widely applied using patterns of linkage disequilibrium (LD) observed in the HapMap panels, but there is a need for alternative methods that can utilize the pooled effect estimates from meta-analyses and explore possible associations with SNPs and haplotypes that are not included in HapMap

Self-Reported Truck Traffic on the Street of Residence and Symptoms of Asthma and Allergic Disease: A Global Relationship in ISAAC Phase 3

BACKGROUND: Associations between traffic pollution on the street of residence and a range of respiratory and allergic outcomes in children have been reported in developed countries, but little is known about such associations in developing countries. METHODS: The third phase of the International Study of Asthma and Allergies in Childhood (ISAAC) was carried out in 13- to 14-year-old and 6- to 7-year-old children across the world. A question about frequency of truck traffic on the street of residence was included in an additional questionnaire. We investigated the association between self-reported truck traffic on the street of residence and symptoms of asthma, rhinoconjunctivitis, and eczema with logistic regression. Adjustments were made for sex, region of the world, language, gross national income, and 10 other subject-specific covariates. RESULTS: Frequency of truck traffic on the street of residence was positively associated with the prevalence of symptoms of asthma, rhinoconjunctivitis, and eczema with an exposure-response relationship. Odds ratios (95% confidence intervals) for "current wheeze" and "almost the whole day" versus "never" truck traffic were 1.35 (1.23-1.49) for 13- to 14-year-olds and 1.35 (1.22-1.48) for 6- to 7-year-olds. CONCLUSIONS: Higher exposure to self-reported truck traffic on the street of residence is associated with increased reports of symptoms of asthma, rhinitis, and eczema in many locations in the world. These findings require further investigation in view of increasing exposure of the world's children to traffic

Evolving UK policy on diversity in the armed services: multiculturalism and its discontents

Reflecting a generally multiculturalist rhetoric, UK policy in this area has hitherto focussed on enhancing the degree to which the armed services represent or reflect the ethnic makeup of the UK population. Ambitious targets have been set and some progress made in moving towards them. However, the dynamics of population change, together with the diverse preferences of ethno-religious minorities, have meant that the goal of representativeness has remained out of reach. At the same time, the armed services have continued to struggle with an ongoing recruitment problem while the volume of operational commitments has shown little sign of reducing

Quantitative analysis of powder mixtures by raman spectrometry : the influence of particle size and its correction

Particle size distribution and compactness have significant confounding effects on Raman signals of powder mixtures, which cannot be effectively modeled or corrected by traditional multivariate linear calibration methods such as partial least-squares (PLS), and therefore greatly deteriorate the predictive abilities of Raman calibration models for powder mixtures. The ability to obtain directly quantitative information from Raman signals of powder mixtures with varying particle size distribution and compactness is, therefore, of considerable interest In this study, an advanced quantitative Raman calibration model was developed to explicitly account for the confounding effects of particle size distribution and compactness on Raman signals of powder mixtures. Under the theoretical guidance of the proposed Raman calibration model, an advanced dual calibration strategy was adopted to separate the Raman contributions caused by the changes in mass fractions of the constituents in powder mixtures from those induced by the variations in the physical properties of samples, and hence achieve accurate quantitative determination for powder mixture samples. The proposed Raman calibration model was applied to the quantitative analysis of backscatter Raman measurements of a proof-of-concept model system of powder mixtures consisting of barium nitrate and potassium chromate. The average relative prediction error of prediction obtained by the proposed Raman calibration model was less than one-third of the corresponding value of the best performing PLS model for mass fractions of barium nitrate in powder mixtures with variations in particle size distribution, as well as compactness

Macropinocytosis renders a subset of pancreatic tumor cells resistant to mTOR inhibition

Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of Pten strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach

Effects of maternal geohelminth infections on allergy in early childhood.

BACKGROUND: Maternal geohelminth infections during pregnancy may protect against allergy development in childhood. OBJECTIVE: We sought to investigate the effect of maternal geohelminths on the development of eczema, wheeze, and atopy during the first 3 years of life. METHODS: A cohort of 2404 neonates was followed to 3 years of age in a rural district in coastal Ecuador. Data on wheeze and eczema were collected by means of questionnaire and physical examination at 13, 24, and 36 months of age. Atopy was measured based on skin prick test (SPT) reactivity to 9 allergens at 36 months. Maternal stool samples were examined for geohelminths by microscopy. Data on potential confounders was collected after birth by questionnaire. RESULTS: Geohelminths were observed in 45.9% of mothers. Eczema and wheeze were reported for 17.7% and 25.9%, respectively, of 2069 (86.1%) children with complete follow-up to 3 years, and allergen SPT reactivity to any allergen was present in 17.2% and to house dust mite in 8.7%. Maternal geohelminth infections were not significantly associated with eczema (adjusted odds ratio [OR], 1.26; 95% CI, 0.98-1.61), wheeze (adjusted OR, 1.02; 95% CI, 0.82-1.27), and SPT reactivity to any allergen (adjusted OR, 0.79; 95% CI, 0.61-1.01). In subgroup analyses maternal geohelminths were associated with a significantly reduced risk of SPT reactivity to mite and other perennial allergens, and maternal ascariasis was associated with an increased risk of eczema and reduced risk of SPT reactivity to all allergens. CONCLUSION: Our data do not support a protective effect of maternal infections with geohelminth parasites during pregnancy against the development of eczema and wheeze in early childhood, although there was evidence in subgroup analyses for a reduction in SPT reactivity to house dust mites and perennial allergens

Construction and analysis of tag single nucleotide polymorphism maps for six human-mouse orthologous candidate genes in type 1 diabetes.

BACKGROUND: One strategy to help identify susceptibility genes for complex, multifactorial diseases is to map disease loci in a representative animal model of the disorder. The nonobese diabetic (NOD) mouse is a model for human type 1 diabetes. Linkage and congenic strain analyses have identified several NOD mouse Idd (insulin dependent diabetes) loci, which have been mapped to small chromosome intervals, for which the orthologous regions in the human genome can be identified. Here, we have conducted re-sequencing and association analysis of six orthologous genes identified in NOD Idd loci: NRAMP1/SLC11A1 (orthologous to Nramp1/Slc11a1 in Idd5.2), FRAP1 (orthologous to Frap1 in Idd9.2), 4-1BB/CD137/TNFRSF9 (orthologous to 4-1bb/Cd137/Tnrfrsf9 in Idd9.3), CD101/IGSF2 (orthologous to Cd101/Igsf2 in Idd10), B2M (orthologous to B2m in Idd13) and VAV3 (orthologous to Vav3 in Idd18). RESULTS: Re-sequencing of a total of 110 kb of DNA from 32 or 96 type 1 diabetes cases yielded 220 single nucleotide polymorphisms (SNPs). Sixty-five SNPs, including 54 informative tag SNPs, and a microsatellite were selected and genotyped in up to 1,632 type 1 diabetes families and 1,709 cases and 1,829 controls. CONCLUSION: None of the candidate regions showed evidence of association with type 1 diabetes (P values > 0.2), indicating that common variation in these key candidate genes does not play a major role in type 1 diabetes susceptibility in the European ancestry populations studied.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Functional divergence in the role of N-linked glycosylation in smoothened signaling

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice