Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 49
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Allergy ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31321783

RESUMO

BACKGROUND: Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome-wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)-induced allergic sensitization and allergic airway inflammation. METHODS: Pag1-deficient (Pag1-/- ) and wild-type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti-CD4 antibody) and adoptive transfer studies. RESULTS: Type 2 inflammation (eosinophilia, eotaxin-2 expression, IL-4/IL-5/IL-13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1-/- mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high-mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte-derived dendritic cell numbers in the mediastinal lymph nodes, and increased T-helper type 2 (TH 2)-cell differentiation. CD4+ T-cell depletion studies or the adoptive transfer of WT OVA-specific CD4+ T cells to WT or Pag1-/- recipients demonstrated that the heightened propensity for TH 2-cell differentiation was both T cell intrinsic and extrinsic. CONCLUSION: PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH 2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.

2.
Am J Hum Genet ; 104(4): 665-684, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929738

RESUMO

The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.

3.
Schizophr Bull ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30452727

RESUMO

Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very large genome-wide association studies of schizophrenia (n = 40675 cases and 64643 controls) and breast cancer (n = 122977 cases and 105974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship. Using LD-score regression, we found that there is a small but significant genetic correlation (rG) between the 2 disorders (rG = 0.14, SE = 0.03, P = 4.75 × 10-8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (SE = 0.009, P = 2.3 × 10-4). A 1 SD increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = -0.005, SE = 0.012, P = .67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results. These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship.

5.
Artigo em Inglês | MEDLINE | ID: mdl-29679657

RESUMO

BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities. OBJECTIVE: We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects. METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study. RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10-6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses. CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.

6.
Sci Rep ; 7(1): 5623, 2017 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-28717140

RESUMO

The involvement of the immune system, particularly the role of T-cells, in sarcoidosis is unclear. The existence of higher CD4+ T-cells and increased CD4/CD8 ratio may indicate a pathogenic role of T-cells in the disease. In this study, we quantified the contribution of T-cells associated variants and of CD4/CD8 ratio in sarcoidosis phenotypes, Löfgren's syndrome (LS) and non- Löfgren's syndrome (non-LS). We employed a polygenic-based approach using genome-wide association studies results on relative levels of T-cells in healthy individuals to measure the genetic contribution of T-cells in sarcoidosis entities. Results revealed that the genetic architecture of LS is highly influenced by genetic variants associated with CD8+ T-cells and CD4/CD8 ratio, explaining up to 7.94% and 6.49% of LS variation, respectively; whereas, the genetic architecture of non-LS is minimally influenced by T-cells, explaining a phenotypic variation of <1%. Moreover, pleiotropy assessment between T-cells and LS/non-LS associated-variants led to the discovery of highly scored pathway maps that shared common factors related to antigen presentation and T-cell regulatory mechanisms. Differences in significant polygenic scores, presence of pleiotropy, and distinct genetic factors provide further insights on how genetic variants and genes associated with relative levels of T-cell subtypes contribute differently to sarcoidosis phenotypes.

7.
J Allergy Clin Immunol ; 139(4): 1148-1157, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27554816

RESUMO

BACKGROUND: Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed. OBJECTIVE: We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. METHODS: We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations. RESULTS: We tested the association between asthma and 17,190 genes that were found to have cis- and/or trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, LIMS1, TINF2, and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13, and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs. CONCLUSION: We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs.


Assuntos
Asma/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Nucleotídeos/genética , Software , Animais , Variação Genética/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , ATPases Mitocondriais Próton-Translocadoras/genética , Nucleotídeos/biossíntese , Locos de Características Quantitativas/genética , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2Y/genética
8.
Clin Transl Immunology ; 6(12): e165, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29333270

RESUMO

Twenty-five genome-wide association studies (GWAS) of asthma were published between 2007 and 2016, the largest with a sample size of 157242 individuals. Across these studies, 39 genetic variants in low linkage disequilibrium (LD) with each other were reported to associate with disease risk at a significance threshold of P<5 × 10-8, including 31 in populations of European ancestry. Results from analyses of the UK Biobank data (n=380 503) indicate that at least 28 of the 31 associations reported in Europeans represent true-positive findings, collectively explaining 2.5% of the variation in disease liability (median of 0.06% per variant). We identified 49 transcripts as likely target genes of the published asthma risk variants, mostly based on LD with expression quantitative trait loci (eQTL). Of these genes, 16 were previously implicated in disease pathophysiology by functional studies, including TSLP, TNFSF4, ADORA1, CHIT1 and USF1. In contrast, at present, there is limited or no functional evidence directly implicating the remaining 33 likely target genes in asthma pathophysiology. Some of these genes have a known function that is relevant to allergic disease, including F11R, CD247, PGAP3, AAGAB, CAMK4 and PEX14, and so could be prioritized for functional follow-up. We conclude by highlighting three areas of research that are essential to help translate GWAS findings into clinical research or practice, namely validation of target gene predictions, understanding target gene function and their role in disease pathophysiology and genomics-guided prioritization of targets for drug development.

9.
BMJ Open ; 6(11): e013856, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27864254

RESUMO

OBJECTIVE: We aimed to investigate the associations of physical activity and change in physical activity with incident asthma in a cohort of Norwegian adults. DESIGN: We conducted a prospective cohort study using data on self-reported physical activity from 3 waves of the Nord-Trøndelag Health Study. Physical activity was reported at the first and second surveys (1985-1986 and 1995-1997). Physical activity was defined from the second survey as inactive or active and the active group was further defined as very low, low, moderate and high. Change in physical activity was defined from the first and second surveys. SETTING: A large population-based health survey in Norway. PARTICIPANTS: We followed 18 894 adults over 11 years who were free from asthma at baseline in 1995-1997. OUTCOME: Incident asthma was reported in the third survey (2006-2008). RESULTS: The cumulative incidence of asthma was 3.6% over the 11 years. The adjusted OR for incident asthma among active participants compared with inactive participants was 0.95 (95% CI 0.69 to 1.34). The adjusted OR for those who were active in the first or second survey versus those who were inactive in both surveys was 0.64 (95% CI 0.34 to 1.38); however, this association was strongly attenuated in sensitivity analysis (OR 0.93, 95% CI 0.38 to 3.09). CONCLUSIONS: We did not observe statistically significant associations of physical activity or change in physical activity with incident asthma in adults over the 11-year follow-up.


Assuntos
Asma/epidemiologia , Exercício , Adulto , Feminino , Seguimentos , Inquéritos Epidemiológicos , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Estudos Prospectivos , Fatores de Risco , Autorrelato
10.
Hum Genet ; 135(7): 827-39, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27155841

RESUMO

Very few studies have investigated the associations between genetic polymorphisms and gene expression on the X-chromosome. This is a major bottleneck when conducting functional follow-up studies of trait-associated variants, as those identified in genome-wide association studies (GWAS). We used a multivariate approach to test the association between individual single nucleotide polymorphisms (SNPs) and exon expression levels measured in 356 Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) from the Geuvadis RNA sequencing project to identify SNPs associated with variation in gene expression on the X-chromosome, which we refer to as eSNPs. At an FDR of 5 %, we discovered 548 independent [linkage disequilibrium (LD) r (2) < 0.1] eSNPs on the X-chromosome. Of these, 35 were in LD (r (2) > 0.8) with previously published disease- or trait-associated variants identified through GWAS. One of the strongest eSNPs identified was rs35975601, which was associated with F8A1 expression (p value = 3 × 10(-20)) and was in LD with a type 1 diabetes risk variant. Additionally, we identified a number of genes for which eSNPs were in LD with multiple diseases or traits, including DNASE1L1 which was mapped to bilirubin levels, type 1 diabetes and schizophrenia. Our results also indicate that multivariate exon-level analysis provides a more powerful approach than univariate gene-level analysis, particularly when SNPs influence the expression of different exons with different magnitude and/or direction of effect. The associations identified in our study may provide new insights into the molecular process by which gene expression may contribute to trait variation or disease risk in humans.


Assuntos
Cromossomos Humanos X/genética , Diabetes Mellitus Tipo 1/genética , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Esquizofrenia/genética , Mapeamento Cromossômico , Diabetes Mellitus Tipo 1/patologia , Éxons , Expressão Gênica , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/patologia
11.
Am J Hum Genet ; 97(2): 329-36, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26211970

RESUMO

The gene(s) whose expression is regulated by allergy risk variants is unknown for many loci identified through genome-wide association studies. Addressing this knowledge gap might point to new therapeutic targets for allergic disease. The aim of this study was to identify the target gene(s) and the functional variant(s) underlying the association between rs7009110 on chromosome 8q21 and allergies. Eight genes are located within 1 Mb of rs7009110. Multivariate association analysis of publicly available exon expression levels from lymphoblastoid cell lines (LCLs) identified a significant association between rs7009110 and the expression of a single gene, PAG1 (p = 0.0017), 732 kb away. Analysis of histone modifications and DNase I hypersensitive sites in LCLs identified four putative regulatory elements (PREs) in the region. Chromosome conformation capture confirmed that two PREs interacted with the PAG1 promoter, one in allele-specific fashion. To determine whether these PREs were functional, LCLs were transfected with PAG1 promoter-driven luciferase reporter constructs. PRE3 acted as a transcriptional enhancer for PAG1 exclusively when it carried the rs2370615:C allergy predisposing allele, a variant in complete linkage disequilibrium with rs7009110. As such, rs2370615, which overlaps RelA transcription factor (TF) binding in LCLs and was found to disrupt Foxo3a binding to PRE3, represents the putative functional variant in this locus. Our studies suggest that the risk-associated allele of rs2370615 predisposes to allergic disease by increasing PAG1 expression, which might promote B cell activation and have a pro-inflammatory effect. Inhibition of PAG1 expression or function might have therapeutic potential for allergic diseases.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cromossomos Humanos Par 8/genética , Regulação da Expressão Gênica/genética , Hipersensibilidade/genética , Proteínas de Membrana/genética , Linfócitos B/imunologia , Estudos de Associação Genética , Humanos , Hipersensibilidade/imunologia , Desequilíbrio de Ligação , Luciferases , Ativação Linfocitária/genética , Análise Multivariada , Conformação de Ácido Nucleico , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Nucleico/genética
12.
J Allergy Clin Immunol ; 136(4): 1065-73, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25930193

RESUMO

BACKGROUND: A variant in the IL-6 receptor (IL-6R) gene increases asthma risk and is predicted to decrease IL-6 classic signaling and increase IL-6 trans-signaling. This suggests that inhibition of IL-6 trans-signaling, but not classic signaling, might suppress allergic airway inflammation. OBJECTIVES: We sought to determine whether IL-6 signaling contributes to (1) acute experimental asthma induced by clinically relevant allergens and (2) variation in asthma clinical phenotypes in asthmatic patients. METHODS: Mice were sensitized to house dust mite (HDM) or cockroach at day 0, treated with IL-6R inhibitors at day 13, and challenged with the same allergen at days 14 to 17. End points were measured 3 hours after the final challenge. IL-6 and soluble IL-6 receptor (sIL-6R) expression in induced sputum of asthmatic patients was correlated with asthma clinical phenotypes. RESULTS: Both HDM and cockroach induced a type 2/type 17 cytokine profile and mixed granulocytic inflammation in the airways. Both allergens increased IL-6 expression in the airways, but only cockroach induced sIL-6R expression. Therefore HDM challenge promoted IL-6 classic signaling but not trans-signaling; in this model treatment with anti-IL-6R did not suppress airway inflammation. In contrast, cockroach-induced inflammation involved activation of IL-6 trans-signaling and production of IL-17A by γδ T cells. Anti-IL-6R, selective blockade of sIL-6R, or γδ T-cell deficiency significantly attenuated cockroach-induced inflammation. Asthmatic patients with high airway IL-6 and sIL-6R levels were enriched for the neutrophilic and mixed granulocytic subtypes. CONCLUSION: Experimental asthma associated with both high IL-6 and high sIL-6R levels in the airways is attenuated by treatment with IL-6R inhibitors.


Assuntos
Asma/imunologia , Interleucina-6/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Interleucina-6/imunologia , Transdução de Sinais/imunologia , Células Th17/imunologia , Células Th2/imunologia , Alérgenos/imunologia , Alérgenos/toxicidade , Animais , Asma/induzido quimicamente , Asma/patologia , Baratas/imunologia , Camundongos , Pyroglyphidae/imunologia , Transdução de Sinais/efeitos dos fármacos , Células Th17/patologia , Células Th2/patologia
13.
Immun Inflamm Dis ; 2(3): 141-51, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25505548

RESUMO

Prevention strategies that delay the onset of asthma may improve clinical outcomes. To identify early life environmental exposures associated with asthma age-of-onset and potential genetic modifiers of these exposures, we studied 1085 subjects with physician-diagnosed asthma and disease onset at or after age two. Subjects reported retrospectively on their exposure to 17 environmental factors before the age of two. The presence of individual or combinations of these early life exposures was then tested for association with variation in asthma age-of-onset. For exposures significantly associated with age-of-onset, we tested if 26 single nucleotide polymorphisms (SNP) with an established association with allergic disease significantly modified the effect of the exposure. Five environmental exposures were significantly associated with variation in asthma age-of-onset after correction for multiple testing: carpet at home (P = 6 × 10(-5)), a serious chest illness (P = 10(-4)), father a cigarette smoker (P = 6 × 10(-4)) and direct exposure to father's smoking (P = 3 × 10(-4)). Individuals with early childhood asthma onset, between the ages of two and six, were 1.4-fold (CI 1.1-1.9) more likely to report having lived in a house with carpet and 2.1-fold (CI 1.3-3.5) more likely to report suffering a serious chest illness before the age of two, than asthmatics with later disease onset. We further found these individual risks to increase to 3.2-fold (CI 1.7-6.0) if carpet exposure and suffering a serious chest illness co-occurred before age two. Paternal smoking exposures were less likely to be reported by asthmatics with early when compared to later disease onset (OR 0.5, CI 0.3-0.7). There were no significant SNP interactions with these environmental exposures after correction for multiple testing. Our results suggest that disease onset in individuals at a high-risk of developing asthma can potentially be delayed by avoiding exposure to carpet at home and preventing serious chest illnesses during the first 2 years of life.

14.
Twin Res Hum Genet ; 17(6): 505-11, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25296694

RESUMO

Asthma and hay fever are likely to share hundreds if not thousands of genetic risk variants. Despite this, the extent to which the power to identify shared risk variants could be improved by considering information from both diseases when designing or analyzing genetic studies has not been studied in detail. Simulations were performed to quantify the power to detect an association between case-control status and a bi-allelic risk variant shared between asthma and hay fever across a range of disease and genetic models, as well as different ascertainment and analytical strategies. For a fixed sample size, when designing a new genome-wide association study (GWAS), selecting for genotyping cases with both asthma and hay fever (A+H+), and controls with neither disease (A-H-) was the study design that provided the greatest power to identify a shared risk variant. On the other hand, when analyzing an existing GWAS, power was greatest across a wide range of scenarios, when cases were defined as individuals who suffered from either disease (A+ or H+) and controls as those who suffered from neither (A-H-). Bivariate analysis of asthma and hay fever provided comparable but slightly decreased power. In conclusion, new GWAS can be designed and existing GWAS reanalyzed more efficiently to identify risk variants for allergic disease by using ascertainment or analytical strategies that consider both asthma and hay fever information.


Assuntos
Asma/genética , Rinite Alérgica Sazonal/genética , Estudos de Casos e Controles , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Medição de Risco
15.
J Allergy Clin Immunol ; 133(6): 1564-71, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24388013

RESUMO

BACKGROUND: To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. OBJECTIVE: We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. METHODS: We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). RESULTS: At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10(-9)) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10(-8)). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10(-7)) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10(-6)). CONCLUSION: By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.


Assuntos
Asma/diagnóstico , Asma/genética , Variação Genética , Estudo de Associação Genômica Ampla , Fenótipo , Locos de Características Quantitativas , Rinite Alérgica Sazonal/diagnóstico , Rinite Alérgica Sazonal/genética , Adulto , Alelos , Asma/complicações , Feminino , Frequência do Gene , Humanos , Lectinas Tipo C/genética , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Proteínas de Transporte de Monossacarídeos/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Rinite Alérgica Sazonal/complicações , Adulto Jovem
16.
Eur Respir J ; 43(4): 983-92, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24311771

RESUMO

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (ß= -0.0452, p=0.024) as well as COPD (ß= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10(-7)), FVC (p=2.07×10(-5)), and FEV1/FVC (p=5.27×10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.


Assuntos
Asma/sangue , Leucócitos/citologia , Pneumopatias/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Telômero/ultraestrutura , Idoso , Asma/genética , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Volume Expiratório Forçado , Humanos , Pneumopatias/genética , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/genética , Análise de Regressão , Fumar , Espirometria , Capacidade Vital
18.
PLoS One ; 7(9): e44008, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23028483

RESUMO

RATIONALE: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. OBJECTIVES: To 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. METHODS: The 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<5 x 10(-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 RESULTS: We 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 (P(Stage1+Stage2) = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P(Stage1+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. CONCLUSIONS: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.


Assuntos
Asma/genética , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Locos de Características Quantitativas , Adulto , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
Stat Appl Genet Mol Biol ; 11(3): Article 6, 2012 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-22499700

RESUMO

In many published genome-wide association studies (GWAS), the top few strongly associated variants are often located in or near known genes. This observation raises the more general hypothesis that variants nominally associated with a phenotype are more likely to overlap genes than those not associated with a phenotype. We developed a simple approach - named GENe OVerlap Analysis (GENOVA) - to formally test this hypothesis. This approach includes two steps. First, we define largely independent groups of highly correlated SNPs (or "clumps") and classify each clump as intersecting a gene or not. Second, we determine how strongly associated each clump is with the phenotype and use logistic regression to formally test the hypothesis that clumps associated with the phenotype are more likely to intersect genes. Simulations suggest that the power of GENOVA is affected by at least three factors: GWAS sample size, the gene boundaries used to define gene-intersecting clumps and the P-value threshold used to define phenotype-associated clumps. We applied GENOVA to results from three recent GWAS meta-analyses of height, body mass index (BMI) and waist-hip ratio (WHR) conducted by the GIANT consortium. SNPs associated with variation in height were 1.44-fold more likely to be in or near genes than SNPs not associated with height (P = 5 x 10⁻²8). A weaker association was observed for BMI (1.09-fold, P = 0.008) and WHR (1.09-fold, P = 0.014). GENOVA is implemented in C++ and is freely available at https://genepi.qimr.edu.au/staff/manuelF/genova/main.html.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Locos de Características Quantitativas , Software , Estatura , Índice de Massa Corporal , Simulação por Computador , Humanos , Internet , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Relação Cintura-Quadril
20.
Bioinformatics ; 28(6): 845-50, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22296789

RESUMO

MOTIVATION: Canonical correlation analysis (CCA) measures the association between two sets of multidimensional variables. We reasoned that CCA could provide an efficient and powerful approach for both univariate and multivariate gene-based tests of association without the need for permutation testing. RESULTS: Compared with a commonly used permutation-based approach, CCA (i) is faster; (ii) has appropriate type-I error rate for normally distributed quantitative traits; (iii) provides comparable power for small to medium-sized genes (<100 kb); (iv) provides greater power when the causal variants are uncommon; (v) provides considerably less power for larger genes (≥100 kb) when the causal variants have a broad minor allele frequency (MAF) spectrum. Application to a GWAS of leukocyte levels identified SAFB and a histone gene cluster as novel putative loci harboring multiple independent variants regulating lymphocyte and neutrophil counts.


Assuntos
Estudo de Associação Genômica Ampla , Análise Multivariada , Frequência do Gene , Humanos , Característica Quantitativa Herdável
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA