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Elliot Israel - One of the best experts on this subject based on the ideXlab platform.
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Genome-wide association studies of Asthma indicate opposite immunopathogenesis direction from autoimmune diseases
The Journal of Allergy and Clinical Immunology, 2012Co-Authors: Xingnan Li, Dara G. Torgerson, Elizabeth J Ampleford, Serpil C. Erzurum, Timothy D Howard, Wendy C Moore, Huashi Li, Mario Castro, William W. Busse, Elliot IsraelAbstract:Background Genome-wide association studies (GWASs) of Asthma have consistently implicated the ORM1-like 3 and gasdermin B (ORMDL3-GSDMB) , IL33 , IL-1 receptor–like 1 and IL-18 receptor 1 (IL1RL1-IL18R1) , RAD50-IL13 , thymic stromal lymphopoietin and WD repeat domain 36 region (TSLP-WDR36) , and HLA-DR/DQ regions. Objective A GWAS of Asthma was performed in a non-Hispanic white population. Methods A GWAS was performed in 813 Severe Asthma Research Program/Collaborative Studies on the Genetics of Asthma/Chicago Asthma Genetics Study cases and 1564 control subjects. The GWAS results were compared with those of the published GWASs of autoimmune diseases. Results Multiple single nucleotide polymorphisms in the TNFAIP3 interacting protein 1 (TNIP1) gene, which interacts with TNFAIP3 and inhibits the TNF-α–induced nuclear factor κB inflammation pathway, were associated with Asthma: rs1422673 ( P = 3.44 × 10 −7 ) and rs10036748 ( P = 1.41 × 10 −6 , r 2 = 0.67). rs1422673 was also associated with Asthma in the published GABRIEL ( P = .018) and EVE ( P = 1.31 × 10 −5 ) studies. The minor allele T of rs20541 in IL13 is the risk allele for Asthma but the protective allele for psoriasis. The minor allele T of rs2395185 in HLA-DRA is the risk allele for Asthma but the protective allele for ulcerative colitis. The minor allele A of rs2872507 in GSDMB is the protective allele for Asthma but the risk allele for rheumatoid arthritis, Crohn disease, and ulcerative colitis. The T allele of rs10036748 in the TNIP1 gene is the minor protective allele for Asthma but the minor or major risk allele for systemic lupus erythematosus and systemic sclerosis in non-Hispanic white or Chinese subjects, respectively. Conclusions Our study suggests that single nucleotide polymorphisms associated with both Asthma and autoimmune diseases might have opposite effects on immunopathogenesis.
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Genome-wide association studies of Asthma indicate opposite immunopathogenesis direction from autoimmune diseases
The Journal of Allergy and Clinical Immunology, 2012Co-Authors: Xingnan Li, Dara G. Torgerson, Elizabeth J Ampleford, Serpil C. Erzurum, Timothy D Howard, Wendy C Moore, Huashi Li, Mario Castro, William W. Busse, Elliot IsraelAbstract:Background Genome-wide association studies (GWASs) of Asthma have consistently implicated the ORM1-like 3 and gasdermin B (ORMDL3-GSDMB) , IL33 , IL-1 receptor–like 1 and IL-18 receptor 1 (IL1RL1-IL18R1) , RAD50-IL13 , thymic stromal lymphopoietin and WD repeat domain 36 region (TSLP-WDR36) , and HLA-DR/DQ regions. Objective A GWAS of Asthma was performed in a non-Hispanic white population. Methods A GWAS was performed in 813 Severe Asthma Research Program/Collaborative Studies on the Genetics of Asthma/Chicago Asthma Genetics Study cases and 1564 control subjects. The GWAS results were compared with those of the published GWASs of autoimmune diseases. Results Multiple single nucleotide polymorphisms in the TNFAIP3 interacting protein 1 (TNIP1) gene, which interacts with TNFAIP3 and inhibits the TNF-α–induced nuclear factor κB inflammation pathway, were associated with Asthma: rs1422673 ( P = 3.44 × 10 −7 ) and rs10036748 ( P = 1.41 × 10 −6 , r 2 = 0.67). rs1422673 was also associated with Asthma in the published GABRIEL ( P = .018) and EVE ( P = 1.31 × 10 −5 ) studies. The minor allele T of rs20541 in IL13 is the risk allele for Asthma but the protective allele for psoriasis. The minor allele T of rs2395185 in HLA-DRA is the risk allele for Asthma but the protective allele for ulcerative colitis. The minor allele A of rs2872507 in GSDMB is the protective allele for Asthma but the risk allele for rheumatoid arthritis, Crohn disease, and ulcerative colitis. The T allele of rs10036748 in the TNIP1 gene is the minor protective allele for Asthma but the minor or major risk allele for systemic lupus erythematosus and systemic sclerosis in non-Hispanic white or Chinese subjects, respectively. Conclusions Our study suggests that single nucleotide polymorphisms associated with both Asthma and autoimmune diseases might have opposite effects on immunopathogenesis.
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The Genetics of Asthma.
Seminars in respiratory and critical care medicine, 2002Co-Authors: Michael E. Wechsler, Elliot IsraelAbstract:Asthma is a complex respiratory disease that, based on familial aggregation studies, has long been recognized to have a significant genetic component. Understanding the Genetics of Asthma is complicated by the fact that there are multiple different pathophysiological mechanisms leading to a complicated heterogeneous phenotype that is difficult to define. It is generally recognized as a complex genetic disease that cannot be explained by single gene models, and in most cases it appears to result from the interaction of multiple genetic and environmental factors. Although linkage and association studies have demonstrated several important relationships between Asthma and a variety of genetic loci, no single gene or group of genes has been definitively demonstrated to be responsible for Asthma. However, population studies, candidate gene approaches, genome-wide screens, and pharmacogenetic studies have all resulted in an increased understanding of the complexities of Asthma Genetics and may lead to better preventive strategies, diagnostic tools, and therapies for this disease.
Lyle J. Palmer - One of the best experts on this subject based on the ideXlab platform.
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Meta-analysis for linkage to Asthma and atopy in the chromosome 5q31–33 candidate region
Human molecular genetics, 2001Co-Authors: Lyle J. Palmer, John W. Holloway, Kathleen C. Barnes, William O.c.m. Cookson, Klaus A. Deichmann, Kevin B Jacobs, Paul R Burton, Robert C Elston, Hong Chen, Tarja LaitinenAbstract:Asthma is a common, complex human disease. Gene discovery in Asthma has been complicated by substantial etiological heterogeneity, the possibility of genes of small effect and the concomitant requirement for large sample sizes. Linkage to Asthma phenotypes has been investigated most intensively in the 5q chromosomal region, although results have been inconsistent across studies and all studies have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis by pooling either summary statistics or raw data. The International Consortium on Asthma Genetics combined data from 11 data sets (n = 6277 subjects) to investigate evidence for linkage of 35 markers spanning the cytokine cluster on chromosome 5q31–33 to 'Asthma' dichotomy and total serum immunoglobulin E (IgE) levels. Chromosome 5q markers typed in different centers were integrated into a consensus map to facilitate effective data pooling. Multipoint linkage analyses using a new Haseman–Elston method were performed with all data sets pooled together, and also separately with the resulting linkage statistics pooled by meta-analytic methods. Our results did not provide any evidence significant at the 5% level that loci conferring susceptibility to Asthma or atopy are present in the 5q31–33 region; however, there was some weak evidence (empirical P = 0.077) of linkage to Asthma affection. This study suggests that loci in 5q31–33 have at most a modest effect on susceptibility to Asthma or total serum IgE levels, may not be detectable or present in all human populations and are difficult to detect even using combined linkage evidence from 2400–2600 full sibling pairs.
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Single region linkage analyses of Asthma: description of data sets
Genetic Epidemiology, 2001Co-Authors: Lyle J. Palmer, John W. Holloway, William O.c.m. Cookson, Klaus A. Deichmann, Tarja LaitinenAbstract:Linkage (genotypic) data from the 5q31-33 candidate region for Asthma were contributed to Genetic Analysis Workshop 12 by members of the International Consortium on Asthma Genetics (COAG). Data came from five independent studies sampled from five countries. Genotypic data for a total of 26 markers were available, although the number of markers typed in each data set varied. Phenotypic and genotypic data was available from a total of 569 families and 3,175 subjects. The phenotypic data available varied among the studies; however information regarding physician-diagnosed Asthma and total serum IgE levels was available in all five studies. This paper describes the ascertainment, data collection methods, phenotypic data, and genotypic data available for the single linkage region analyses undertaken for Genetic Analysis Workshop 12.
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a retrospective collaboration on chromosome 5 by the international consortium on Asthma Genetics coag
Clinical & Experimental Allergy, 2001Co-Authors: John W. Holloway, Kathleen C. Barnes, Lyle J. Palmer, William O.c.m. Cookson, Klaus A. Deichmann, Tarja Laitinen, C Lonjou, H Chen, M WjstAbstract:Asthma is the most common chronic childhood disease in developed nations [ 1], affecting more than 155 million individuals. The cost of treating the disease in the USA alone approximates 6 billion dollars per annum [ 2]. Asthma is a complex disease that has proven extremely difficult to dissect genetically [ 3]. Considerable effort is currently being expended in attempts to detect genetic loci contributing to Asthma susceptibility [ 4–7], with the ultimate goal of improving preventive strategies, diagnostic tools and therapies. However, no specific major gene exhibiting functional effects has been mapped to date.
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A retrospective collaboration on chromosome 5 by the International Consortium on Asthma Genetics (COAG): Special report
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2001Co-Authors: Lyle J. Palmer, John W. Holloway, Kathleen C. Barnes, M Wjst, Klaus A. Deichmann, Tarja Laitinen, C Lonjou, H Chen, W. Cookson, Newton E. MortonAbstract:Asthma is the most common chronic childhood disease in developed nations [ 1], affecting more than 155 million individuals. The cost of treating the disease in the USA alone approximates 6 billion dollars per annum [ 2]. Asthma is a complex disease that has proven extremely difficult to dissect genetically [ 3]. Considerable effort is currently being expended in attempts to detect genetic loci contributing to Asthma susceptibility [ 4–7], with the ultimate goal of improving preventive strategies, diagnostic tools and therapies. However, no specific major gene exhibiting functional effects has been mapped to date.
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pooling data and linkage analysis in the chromosome 5q candidate region for Asthma
Genetic Epidemiology, 2001Co-Authors: Kevin B Jacobs, Paul R Burton, Sudha K Iyengar, Robert C Elston, Lyle J. PalmerAbstract:We investigated a variety of methods for pooling data from eight data sets (n = 5,424 subjects) to validate evidence for linkage of markers in the cytokine cluster on chromosome 5q31-33 to Asthma and Asthma-associated phenotypes. Chromosome 5 markers were integrated into current genetic linkage and physical maps, and a consensus map was constructed to facilitate effective data pooling. To provide more informative phenotypes with better distributional properties, variance component models were fitted using Gibbs sampling methods in order to generate residual additive genetic effects, or sigma-squared-A-random-effects (SSARs), which were used as derived phenotypes in subsequent linkage analyses. Multipoint estimates of alleles shared identically by descent (IBD) were computed for all full sibling pairs. Linkage analyses were performed with a new Haseman-Elston method that uses generalized-least-squares and a weighted combination of the mean-corrected trait-sum squared and trait-difference squared as the dependent variable. Analyses were performed with all data sets pooled together, and also separately with the resulting linkage statistics pooled by several meta-analytic methods. Our results provide no significant evidence that loci conferring susceptibility to Asthma affection or atopy, as measured by total serum IgE levels, are present in the 5q31-33 region. This study has provided a clearer understanding of the significance, or lack of significance, of the 5q31-33 region in Asthma Genetics for the phenotypes studied.
Rasika A. Mathias - One of the best experts on this subject based on the ideXlab platform.
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Genome-wide interaction studies reveal sex-specific Asthma risk alleles
Human molecular genetics, 2014Co-Authors: Rachel A. Myers, Rasika A. Mathias, Nicole M. Scott, W. James Gauderman, Weiliang Qiu, Isabelle Romieu, Albert M. Levin, Maria Pino-yanes, Penelope E. Graves, Albino Barraza VillarrealAbstract:Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on Asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific Asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male Asthma cases, 2566 female Asthma cases and 3830 non-Asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific Asthma risk loci had P-values < 1 × 10−6, of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with Asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific Asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in Asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.
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Introduction to Genetics and Genomics in Asthma: Genetics of Asthma
Advances in experimental medicine and biology, 2013Co-Authors: Rasika A. MathiasAbstract:While Asthma is a heterogeneous disease, a strong genetic basis has been firmly established. Rather than being a single disease entity, Asthma consists of related, overlapping syndromes [Barnes (Proc Am Thor Soc 8:143-148, 2011)] including three general domains: variable airway obstruction, airway hyper-responsiveness, and airway inflammation with a considerable proportion, but not all, of Asthma being IgE-mediated further adding to its heterogeneity. This chapter reviews the approaches to the elucidation of Genetics of Asthma from the early evidence of familial clustering to the current state of knowledge with genome-wide approaches. The conclusion is that research efforts have led to a tremendous repository of genetic determinants of Asthma, most of which fall into the above phenotypic domains of the syndrome. We now look to future integrative approaches of Genetics, genomics (Chap. 10), and epiGenetics (Chap. 11) to better understand the causal mechanism through which, these genetic loci act in manifesting Asthma.
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A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations
The Journal of allergy and clinical immunology, 2012Co-Authors: Albert M. Levin, Blanca E. Himes, Rasika A. Mathias, Rachel A. Myers, Isabelle Romieu, Liling Huang, Lindsey A. Roth, Denise Daley, Mao Yang, Celeste EngAbstract:Background IgE is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino subjects have not been well represented in genetic studies of total IgE. Objective We sought to identify the genetic predictors of serum total IgE levels. Methods We used genome-wide association data from 4292 subjects (2469 African Americans, 1564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (ie, African American, Latino, and European American) and Asthma status. The resulting P values were meta-analyzed, accounting for sample size and direction of effect. Top single nucleotide polymorphism associations from the meta-analysis were reassessed in 6 additional cohorts comprising 5767 subjects. Results We identified 10 unique regions in which the combined association statistic was associated with total serum IgE levels ( P −6 ) and the minor allele frequency was 5% or greater in 2 or more population groups. Variant rs9469220, corresponding to HLA-DQB1 , was the single nucleotide polymorphism most significantly associated with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined ( P = .007 and 2.45 × 10 −7 , respectively). In addition, findings from earlier genome-wide association studies were also validated in the current meta-analysis. Conclusion This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE levels in multiple race-ethnic groups. This study also extends and confirms the findings of earlier genome-wide association analyses in African American and Latino subjects.
Kathleen C. Barnes - One of the best experts on this subject based on the ideXlab platform.
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Ancestry, ancestry-informative markers, Asthma, and the quest for personalized medicine
The Journal of allergy and clinical immunology, 2010Co-Authors: Kathleen C. BarnesAbstract:Conventional wisdom regarding the ultimate utility of human genome discoveries in common complex diseases such as Asthma is that with the discovery of genetic polymorphisms that track with specific clinical traits, genetic profiling for personalized medicine will eventually be realized and lead to improvements in the prognosis and prediction of disease in the clinical setting. Acknowledging that few such discoveries have resulted in reliably predictive tests thus far, beyond some of the Mendelian disorders (ie, Huntington disease and phenylketonuria) and perhaps a handful of common diseases (ie, hypertriglyceridemia and age-related macular degeneration), genome-based prediction of common diseases like Asthma is nevertheless anticipated in the long-term. The tremendous investment committed to the field of Asthma Genetics over the past 2 decades, spanning from the early linkage and candidate gene studies in the early 1990s and into the 21st century to the dozen or so Asthma genome-wide association studies performed in just the past few years, is testimony to our confidence in the ‘‘gene hunters.’’ It is well established and has been demonstrated year after year in survey after survey that Asthmatic subjects of African descent have greater Asthmamorbidity andmortality than white subjects, but the extent to which genetic variation contributes to these profound racial and ethnic disparities has not been so clear. Reports of increases in the prevalence and severity of Asthma according to African ancestry outside of the United States further support a role for a genetic contribution that is dictated, at least in part, by one’s biogeography. Although race and ethnicity are undeniably social constructs reflective of an individual’s self-ascribed sociocultural, psychological, behavioral, and biological identity, the striking racial and ethnic disparities in disease prevalence and severity for common complex disorders, such as Asthma, cannot be explained entirely by ‘‘nongenetic’’ factors. Indeed, however one chooses (or chooses not) to define the biological construct of race, in the case of Asthma, substantial variation in frequencies of high-risk genetic variants according to ancestry has been well established. This has been of special interest in the field of pharmacoGenetics, in which genetic variation in response to treatment according to self-reported race/ethnicity is suspected.
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Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study
The Journal of allergy and clinical immunology, 2005Co-Authors: April Zambelli-weiner, Eva Ehrlich, Maria L. Stockton, Audrey V. Grant, Shu Zhang, Paul N. Levett, Terri H. Beaty, Kathleen C. BarnesAbstract:Background Both a functional promoter polymorphism in the gene encoding CD14 (C-260T) and exposure to endotoxin are believed to play key roles in modulating the immune response and expression of atopic disease. Objective We aimed to evaluate the role of the CD14 C-260T polymorphism in a population of African descent and to test for interaction between this genotype and house dust endotoxin (HDE) exposure on atopic phenotypes. Methods Asthmatic probands and their families were recruited as part of the Barbados Asthma Genetics Study. The C-260T polymorphism and two additional CD14 promoter markers (G-1461T, C-1721T) were genotyped. Endotoxin was measured in house dust samples. Results Using a Family-Based Association Test, the C-260T allele appeared to be protective against Asthma ( z =−2.444; P =.015) and Asthma severity ( z =−2.615; P =.009) under a recessive model. No significant associations were observed for the G-1461T and C-1721T markers both individually and in haplotypes. In a case-control analysis, the CD14 TT genotype was found to reduce risk of Asthma compared with the CD14 CC/CT genotypes (odds ratio [OR], 0.26; 95% CI, 0.14-0.49) and was associated with lower Asthma severity scores ( P Conclusion These data suggest that the CD14-260 polymorphism may play a role in controlling risk to atopic disease and underscore the importance of incorporating key environmental exposures into studies of genetic risk factors.
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Meta-analysis for linkage to Asthma and atopy in the chromosome 5q31–33 candidate region
Human molecular genetics, 2001Co-Authors: Lyle J. Palmer, John W. Holloway, Kathleen C. Barnes, William O.c.m. Cookson, Klaus A. Deichmann, Kevin B Jacobs, Paul R Burton, Robert C Elston, Hong Chen, Tarja LaitinenAbstract:Asthma is a common, complex human disease. Gene discovery in Asthma has been complicated by substantial etiological heterogeneity, the possibility of genes of small effect and the concomitant requirement for large sample sizes. Linkage to Asthma phenotypes has been investigated most intensively in the 5q chromosomal region, although results have been inconsistent across studies and all studies have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis by pooling either summary statistics or raw data. The International Consortium on Asthma Genetics combined data from 11 data sets (n = 6277 subjects) to investigate evidence for linkage of 35 markers spanning the cytokine cluster on chromosome 5q31–33 to 'Asthma' dichotomy and total serum immunoglobulin E (IgE) levels. Chromosome 5q markers typed in different centers were integrated into a consensus map to facilitate effective data pooling. Multipoint linkage analyses using a new Haseman–Elston method were performed with all data sets pooled together, and also separately with the resulting linkage statistics pooled by meta-analytic methods. Our results did not provide any evidence significant at the 5% level that loci conferring susceptibility to Asthma or atopy are present in the 5q31–33 region; however, there was some weak evidence (empirical P = 0.077) of linkage to Asthma affection. This study suggests that loci in 5q31–33 have at most a modest effect on susceptibility to Asthma or total serum IgE levels, may not be detectable or present in all human populations and are difficult to detect even using combined linkage evidence from 2400–2600 full sibling pairs.
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a retrospective collaboration on chromosome 5 by the international consortium on Asthma Genetics coag
Clinical & Experimental Allergy, 2001Co-Authors: John W. Holloway, Kathleen C. Barnes, Lyle J. Palmer, William O.c.m. Cookson, Klaus A. Deichmann, Tarja Laitinen, C Lonjou, H Chen, M WjstAbstract:Asthma is the most common chronic childhood disease in developed nations [ 1], affecting more than 155 million individuals. The cost of treating the disease in the USA alone approximates 6 billion dollars per annum [ 2]. Asthma is a complex disease that has proven extremely difficult to dissect genetically [ 3]. Considerable effort is currently being expended in attempts to detect genetic loci contributing to Asthma susceptibility [ 4–7], with the ultimate goal of improving preventive strategies, diagnostic tools and therapies. However, no specific major gene exhibiting functional effects has been mapped to date.
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A retrospective collaboration on chromosome 5 by the International Consortium on Asthma Genetics (COAG): Special report
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2001Co-Authors: Lyle J. Palmer, John W. Holloway, Kathleen C. Barnes, M Wjst, Klaus A. Deichmann, Tarja Laitinen, C Lonjou, H Chen, W. Cookson, Newton E. MortonAbstract:Asthma is the most common chronic childhood disease in developed nations [ 1], affecting more than 155 million individuals. The cost of treating the disease in the USA alone approximates 6 billion dollars per annum [ 2]. Asthma is a complex disease that has proven extremely difficult to dissect genetically [ 3]. Considerable effort is currently being expended in attempts to detect genetic loci contributing to Asthma susceptibility [ 4–7], with the ultimate goal of improving preventive strategies, diagnostic tools and therapies. However, no specific major gene exhibiting functional effects has been mapped to date.
Klaus A. Deichmann - One of the best experts on this subject based on the ideXlab platform.
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Confirmation of association of IL-15 with pediatric Asthma and comparison of different controls.
Allergy, 2006Co-Authors: Sibylle Bierbaum, Klaus A. Deichmann, Renate Nickel, S. Zitnik, I. Ahlert, Susanne Lau, Ulrich Wahn, Andrea HeinzmannAbstract:Background: Interleukin (IL)-15 is an important mediator in chronic inflammatory diseases. Recently, we have described the association of IL-15 haplotypes with bronchial Asthma. Asthma Genetics is highly complex – about every second candidate gene is not confirmed in consecutive studies. We were interested in whether association of Asthma with IL-15 holds in a second population. Furthermore, we sought to investigate the effect of different controls. Methods: Five IL-15 polymorphisms were genotyped on the German Multicenter Allergy Study (MAS) cohort consisting of 886 children who were followed up from birth to 10 years of age. At 10 years of age, 96 were found to be Asthmatic. MAS children who never had any wheezing symptoms (n = 576), who were never diagnosed with Asthma (n = 790) and 129 super controls who had never had any atopic disorder were used as controls. Finally, 270 randomly chosen adults served as controls. Results: Association was confirmed with single polymorphism and haplotypes. The super controls showed the highest difference to the Asthmatics regarding haplotype frequencies. However, the effect escaped statistical significance, most likely because of the small sample size. Conclusion: Association of IL-15 with Asthma was confirmed. Although super controls might be the most suitable, more numbers are needed. This might hamper the value of these controls especially when investigating common diseases.
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Genes for atopy and Asthma.
Current opinion in allergy and clinical immunology, 2001Co-Authors: Andrea Heinzmann, Klaus A. DeichmannAbstract:The genetic basis of atopic diseases is represented by a complex network of interacting genes or common genetic variants rather than a few disease-causing mutations. The individual risk of developing Asthma or other atopic diseases is defined by the concert of interaction of these hereditary factors and environmental stimuli. The first decade of Asthma Genetics has been spent identifying those genetic regions through linkage analysis, which are likely to harbour Asthma genes. At the same time, several candidate genes for Asthma and atopy have been identified and their variants characterized, some of them even to a level of functional understanding. Rather than adding new candidate regions and genes to the pool of knowledge, the interest in the past year has moved to a more sophisticated statistical evaluation of the given linkage and association data and a more precise definition of so-called 'intermediate phenotypes'. Some of the results are quite surprising and have helped us to understand the underlying pathophysiology. For example, the distinct clinical traits of Asthma, such as atopic sensitization or inflammation of the bronchial epithelium, seem to be defined by distinct subsets of predisposing genes. At the same time, the very same subsets of genes might underlie further clinical diseases with similar clinical features. Polymorphisms within IL-4R alpha, which had been shown to be associated with Asthma and atopy, have also been shown to be associated with kidney allograft rejection, systemic lupus erythematosus and Crohn's disease. There might thus just be a few Asthma and atopy genes. Finally, Asthma and atopy Genetics has now reached a point of practical application. The Genetics of susceptibility to environmental stimuli, pharmacogenetic data, and the advent of new pharmaceutical targets will greatly influence the whole field of Asthma and atopy.
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Meta-analysis for linkage to Asthma and atopy in the chromosome 5q31–33 candidate region
Human molecular genetics, 2001Co-Authors: Lyle J. Palmer, John W. Holloway, Kathleen C. Barnes, William O.c.m. Cookson, Klaus A. Deichmann, Kevin B Jacobs, Paul R Burton, Robert C Elston, Hong Chen, Tarja LaitinenAbstract:Asthma is a common, complex human disease. Gene discovery in Asthma has been complicated by substantial etiological heterogeneity, the possibility of genes of small effect and the concomitant requirement for large sample sizes. Linkage to Asthma phenotypes has been investigated most intensively in the 5q chromosomal region, although results have been inconsistent across studies and all studies have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis by pooling either summary statistics or raw data. The International Consortium on Asthma Genetics combined data from 11 data sets (n = 6277 subjects) to investigate evidence for linkage of 35 markers spanning the cytokine cluster on chromosome 5q31–33 to 'Asthma' dichotomy and total serum immunoglobulin E (IgE) levels. Chromosome 5q markers typed in different centers were integrated into a consensus map to facilitate effective data pooling. Multipoint linkage analyses using a new Haseman–Elston method were performed with all data sets pooled together, and also separately with the resulting linkage statistics pooled by meta-analytic methods. Our results did not provide any evidence significant at the 5% level that loci conferring susceptibility to Asthma or atopy are present in the 5q31–33 region; however, there was some weak evidence (empirical P = 0.077) of linkage to Asthma affection. This study suggests that loci in 5q31–33 have at most a modest effect on susceptibility to Asthma or total serum IgE levels, may not be detectable or present in all human populations and are difficult to detect even using combined linkage evidence from 2400–2600 full sibling pairs.
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Single region linkage analyses of Asthma: description of data sets
Genetic Epidemiology, 2001Co-Authors: Lyle J. Palmer, John W. Holloway, William O.c.m. Cookson, Klaus A. Deichmann, Tarja LaitinenAbstract:Linkage (genotypic) data from the 5q31-33 candidate region for Asthma were contributed to Genetic Analysis Workshop 12 by members of the International Consortium on Asthma Genetics (COAG). Data came from five independent studies sampled from five countries. Genotypic data for a total of 26 markers were available, although the number of markers typed in each data set varied. Phenotypic and genotypic data was available from a total of 569 families and 3,175 subjects. The phenotypic data available varied among the studies; however information regarding physician-diagnosed Asthma and total serum IgE levels was available in all five studies. This paper describes the ascertainment, data collection methods, phenotypic data, and genotypic data available for the single linkage region analyses undertaken for Genetic Analysis Workshop 12.
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a retrospective collaboration on chromosome 5 by the international consortium on Asthma Genetics coag
Clinical & Experimental Allergy, 2001Co-Authors: John W. Holloway, Kathleen C. Barnes, Lyle J. Palmer, William O.c.m. Cookson, Klaus A. Deichmann, Tarja Laitinen, C Lonjou, H Chen, M WjstAbstract:Asthma is the most common chronic childhood disease in developed nations [ 1], affecting more than 155 million individuals. The cost of treating the disease in the USA alone approximates 6 billion dollars per annum [ 2]. Asthma is a complex disease that has proven extremely difficult to dissect genetically [ 3]. Considerable effort is currently being expended in attempts to detect genetic loci contributing to Asthma susceptibility [ 4–7], with the ultimate goal of improving preventive strategies, diagnostic tools and therapies. However, no specific major gene exhibiting functional effects has been mapped to date.
