27 results found
Saad NJ, Kaakinen M, Da Silva Couto Alves A, et al., 2013, Forced vital capacity, systemic inflammation and cardiometabolic markers in adulthood: a cross-sectional analysis, British Thoracic Society Winter Meeting 2013
Alves AC, Bruhn S, Ramasamy A, et al., 2013, Dysregulation of complement system and CD4+T cell activation pathways implicated in allergic response, PLoS One, Vol: 8, Pages: 1-15, ISSN: 1932-6203
Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13) and of the Th2 master regulator (GATA3), suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1) are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data.
Bonnelykke K, Matheson MC, Pers TH, et al., 2013, Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization, NATURE GENETICS, Vol: 45, Pages: 902-U290, ISSN: 1061-4036
Thun GA, Imboden M, Ferrarotti I, et al., 2013, Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels, PLoS Genetics, Vol: 9, Pages: 1-16, ISSN: 1553-7390
Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1–5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in t
Stets MI, Pinto AS, Huergo LF, et al., 2013, Rapid identification of bacterial isolates from wheat roots by high resolution whole cell MALDI-TOF MS analysis, Journal of Biotechnology, Vol: 165, Pages: 167-174, ISSN: 0168-1656
Couto-Alves A, Wright VJ, Perumal K, et al., 2013, A new scoring system derived from base excess and platelet count at presentation predicts mortality in paediatric meningococcal sepsis, CRITICAL CARE, Vol: 17, ISSN: 1466-609X
Ramasamy A, Kuokkanen M, Vedantam S, et al., 2012, Genome-wide association studies of asthma in population-based cohorts confirm known and suggested loci and identify an additional association near HLA, PLoS One, Vol: 7, Pages: 1-10, ISSN: 1932-6203
RationaleAsthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies.ObjectivesTo test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations.MethodsThe APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10−8) and three variants reported as suggestive (P<5×10−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever.Main ResultsWe observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status.ConclusionsPopulation-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
Barrenas F, Chavali S, Alves AC, et al., 2012, Highly interconnected genes in disease-specific networks are enriched for disease-associated polymorphisms, Genome Biology, Vol: 13, Pages: R46-R46, ISSN: 1474-7596
BackgroundComplex diseases are associated with altered interactions between thousands of genes. We developed a novel method to identify and prioritize disease genes, which was generally applicable to complex diseases.ResultsWe identified modules of highly interconnected genes in disease-specific networks derived from integrating gene-expression and protein interaction data. We examined if those modules were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies. First, we analyzed publicly available gene expression microarray and genome-wide association study (GWAS) data from 13, highly diverse, complex diseases. In each disease, highly interconnected genes formed modules, which were significantly enriched for genes harboring disease-associated SNPs. To test if such modules could be used to find novel genes for functional studies, we repeated the analyses using our own gene expression microarray and GWAS data from seasonal allergic rhinitis. We identified a novel gene, FGF2, whose relevance was supported by functional studies using combined small interfering RNA-mediated knock-down and gene expression microarrays. The modules in the 13 complex diseases analyzed here tended to overlap and were enriched for pathways related to oncological, metabolic and inflammatory diseases. This suggested that this union of the modules would be associated with a general increase in susceptibility for complex diseases. Indeed, we found that this union was enriched with GWAS genes for 145 other complex diseases.ConclusionsModules of highly interconnected complex disease genes were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies.
Alves AC, Li JV, Garcia-Perez I, et al., 2012, Characterization of data analysis methods for information recovery from metabolic 1 H NMR spectra using artificial complex mixtures, Metabolomics, Pages: 1-11
El-Sayed Moustafa JS, Eleftherohorinou H, de Smith AJ, et al., 2012, Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity, Hum Mol Genet, Vol: 21, Pages: 3727-3738, ISSN: 1460-2083
Variable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (P(empirical)= 8.9 x 10(-8) and P= 3.1 x 10(-3), respectively) which we estimate explains ~0.8% of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46% of the variance (P(combined)= 1.6 x 10(-3)). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P= 0.027) and both VNTRs (P(empirical)= 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies.
Alves AC, Li JV, Garcia-Perez I, et al., 2012, Characterization of data analysis methods for information recovery from metabolic 1H NMR spectra using artificial complex mixtures, Metabolomics, Vol: 8, Pages: 1170-1180
Paternoster L, Standl M, Chen CM, et al., 2011, Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis, Nature Genetics, Vol: 44, Pages: 187-192, ISSN: 1546-1718
Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 x 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 x 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 x 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
Masson P, Alves AC, Ebbels TMD, et al., 2010, Optimization and evaluation of metabolite extraction protocols for untargeted metabolic profiling of liver samples by UPLC-MS, Analytical chemistry
Faoro H, Alves AC, Souza EM, et al., 2010, Influence of soil characteristics on the diversity of bacteria in the Southern Brazilian Atlantic Forest, Applied and environmental microbiology, Vol: 76, Pages: 4744-4749
Couto Alves A, Rantalainen M, Holmes E, et al., 2009, Analytic properties of statistical total correlation spectroscopy based information recovery in 1H NMR metabolic data sets, Analytical chemistry, Vol: 81, Pages: 2075-2084
Garcia-Perez I, Couto Alves A, Angulo S, et al., 2009, Bidirectional correlation of NMR and capillary electrophoresis fingerprints: a new approach to investigating Schistosoma mansoni infection in a mouse model, Analytical chemistry, Vol: 82, Pages: 203-210
Alves A, Camacho R, Oliveira E, 2008, Model Validation: A statistical-based criterium of hypotheses acceptance in numerical reasoning, Proc. 14th Int. Conf. Inductive Logic Program
Okun O, Zagoruiko N, Alves A, et al., 2006, Selection of more than one gene at a time for cancer prediction from gene expression data, this volume
Okun O, Priisalu H, Alves A, 2005, Fast non-negative dimensionality reduction for protein fold recognition, Machine Learning: ECML 2005, Pages: 665-672
Camacho R, Alves A, Costa JP, et al., 2005, Chapter 5-Computational Methods in Bioinformatics (CMB 2005)-Introduction, Lecture Notes in Computer Science, Vol: 3808, Pages: 235-235
Alves A, Zagoruiko N, Okun O, et al., 2005, Predictive analysis of gene expression data from human sage libraries, Proceedings of the ECML/PKDD Discovery Challenge Workshop, Pages: 60-71
Camacho R, Alves A, da Costa JP, et al., 2005, CMB’05: Workshop on Computational Methods in Bioinformatics, Pages: 129-129
Alves A, Camacho R, Oliveira E, 2004, Improving numerical reasoning capabilities of Inductive Logic Programming systems, Advances in Artificial Intelligence–IBERAMIA 2004, Pages: 195-204
Alves A, Camacho R, Oliveira E, 2004, Inductive Logic Programming for Data Mining in Economics, Proc. of the 2nd International Workshop on Data Mining and Adaptive Modeling Methods for Economics and Management, Pisa
Alves A, Camacho R, Oliveira E, 2004, Machine Learning and Knowledge Acquisition-Improving Numerical Reasoning Capabilities of Inductive Logic Programming Systems, Lecture Notes in Computer Science, Vol: 3315, Pages: 195-204
Alves A, Camacho R, Oliveira E, 2004, Discovery of functional relationships in multi-relational data using inductive logic programming, Pages: 319-322
Alves A, Camacho R, Oliveira E, 2003, Learning time series models with inductive logic programming, Proceedings de EUROPEAN SYMPOSIUM ON INTELLIGENT TECHNOLOGIES, HYBRID SYSTEMS AND THEIR IMPLEMENTATION ON SMART ADAPTIVE SYSTEMS, EUNITE 2003
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