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Dive into the research topics where Michael Kabesch is active.

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Featured researches published by Michael Kabesch.


Nature | 2007

Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.

Miriam F. Moffatt; Michael Kabesch; Liming Liang; Anna L. Dixon; David P. Strachan; Simon Heath; Martin Depner; Andrea von Berg; Albrecht Bufe; Ernst Rietschel; Andrea Heinzmann; Burkard Simma; Thomas Frischer; Saffron A. G. Willis-Owen; Kenny C. C. Wong; Thomas Illig; Christian Vogelberg; Stephan K. Weiland; Erika von Mutius; Gonçalo R. Abecasis; Martin Farrall; Ivo Gut; G. Mark Lathrop; William Cookson

Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.


Nature Genetics | 2003

Positional cloning of a novel gene influencing asthma from chromosome 2q14

Maxine Allen; Andrea Heinzmann; Gonçalo R. Abecasis; John Broxholme; Chris P. Ponting; Sumit Bhattacharyya; Jon Tinsley; Youming Zhang; Richard Holt; E. Yvonne Jones; Nick Lench; Alisoun H. Carey; Helene Jones; Nicholas J. Dickens; Claire Dimon; Rosie Nicholls; Crystal Baker; Luzheng Xue; Elizabeth Townsend; Michael Kabesch; Stephan K. Weiland; David Carr; Erika von Mutius; Ian M. Adcock; Peter J. Barnes; G. Mark Lathrop; M Edwards; Miriam F. Moffatt; William Cookson

Asthma is a common disease in children and young adults. Four separate reports have linked asthma and related phenotypes to an ill-defined interval between 2q14 and 2q32 (refs. 1–4), and two mouse genome screens have linked bronchial hyper-responsiveness to the region homologous to 2q14 (refs. 5,6). We found and replicated association between asthma and the D2S308 microsatellite, 800 kb distal to the IL1 cluster on 2q14. We sequenced the surrounding region and constructed a comprehensive, high-density, single-nucleotide polymorphism (SNP) linkage disequilibrium (LD) map. SNP association was limited to the initial exons of a solitary gene of 3.6 kb (DPP10), which extends over 1 Mb of genomic DNA. DPP10 encodes a homolog of dipeptidyl peptidases (DPPs) that cleave terminal dipeptides from cytokines and chemokines, and it presents a potential new target for asthma therapy.


The Journal of Allergy and Clinical Immunology | 2008

Filaggrin mutations, atopic eczema, hay fever, and asthma in children

Stephan Weidinger; Maureen J. O'Sullivan; Thomas Illig; Hansjörg Baurecht; Martin Depner; Elke Rodriguez; Andreas Ruether; Norman Klopp; Christian Vogelberg; Stephan K. Weiland; W.H. Irwin McLean; Erika von Mutius; Alan D. Irvine; Michael Kabesch

BACKGROUND Mutations in the filaggrin gene (FLG) have been shown to play a significant role in ichthyosis vulgaris and eczema, 2 common chronic skin diseases. However, their role in the development of other atopic diseases such as asthma and rhinitis has not yet been clarified in large population-based studies. OBJECTIVES To study the effect of FLG mutations at the population level and their effect on other atopic phenotypes. METHODS Association analysis of the 2 common FLG-null mutations R501X and 2282del4 and 3 recently identified rare FLG variants (R2447X, S3247X, 3702delG) was performed on our cross-sectional population of German children (n = 3099) recruited as part of the International Study of Asthma and Allergies in Childhood II in Munich (n = 1159) and Dresden (n = 1940). RESULTS FLG variants increased the risk for eczema more than 3-fold (odds ratio [OR], 3.12; 95% CI, 2.33-4.173; P = 2.5 x 10(-14); population-attributable risk, 13.5%). Independent of eczema, FLG mutations conferred a substantial risk for allergic rhinitis (OR, 2.64; 95% CI, 1.76-4.00; P = 2.5 x 10(-6); population-attributable risk, 10.8%). Nasal biopsies demonstrated strong filaggrin expression in the cornified epithelium of the nasal vestibular lining, but not the transitional and respiratory nasal epithelia. In contrast, the association with asthma (OR, 1.79; 95% CI, 1.19-2.68; P = .0048) was restricted to asthma occurring in the context of eczema, and there was a strong association with the complex phenotype eczema plus asthma (OR, 3.49; 95% CI, 2.00-6.08; P = 1.0 x 10(-5)). CONCLUSION Our results suggest that FLG mutations are key organ specific factors predominantly affecting the development of eczema and confer significant risks of allergic sensitization and allergic rhinitis as well as asthma in the context of eczema.


The New England Journal of Medicine | 2010

Variants of DENND1B Associated with Asthma in Children

Patrick Sleiman; James H. Flory; Marcin Imielinski; Jonathan P. Bradfield; Kiran Annaiah; Saffron A. G. Willis-Owen; Kai Wang; Nicholas Rafaels; Sven Michel; Klaus Bønnelykke; Haitao Zhang; Cecilia E. Kim; Edward C. Frackelton; Joseph T. Glessner; Cuiping Hou; F. George Otieno; Erin Santa; Kelly Thomas; Ryan M. Smith; Wendy Glaberson; Maria Garris; Rosetta M. Chiavacci; Terri H. Beaty; Ingo Ruczinski; Jordan M. Orange; Julian L. Allen; Jonathan M. Spergel; Robert W. Grundmeier; Rasika A. Mathias; Jason D. Christie

BACKGROUND Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10(-13) for the comparison across all samples). The 1q31 locus contains the 1q31 locus contains DENND1B, a gene expressed by natural killer cells and dendritic cells. DENND1B protein is predicted to interact with the tumor necrosis factor α receptor [corrected]. CONCLUSIONS We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.


PLOS Genetics | 2008

Genome-Wide Scan on Total Serum IgE Levels Identifies FCER1A as Novel Susceptibility Locus

Stephan Weidinger; Christian Gieger; Elke Rodriguez; Hansjörg Baurecht; Martin Mempel; Norman Klopp; Henning Gohlke; Stefan Wagenpfeil; Markus Ollert; Johannes Ring; Heidrun Behrendt; Joachim Heinrich; Natalija Novak; Thomas Bieber; Ursula Krämer; Dietrich Berdel; Andrea von Berg; Carl Peter Bauer; Olf Herbarth; Sibylle Koletzko; Holger Prokisch; Divya Mehta; Thomas Meitinger; Martin Depner; Erika von Mutius; Liming Liang; Miriam F. Moffatt; William Cookson; Michael Kabesch; H.-Erich Wichmann

High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85×10−20 and 7.08×10−19 in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78×10−4 and P = 1.95×10−3). The “top” SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28×10−7−4.46×10−8) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.


Thorax | 2004

Glutathione S transferase deficiency and passive smoking increase childhood asthma

Michael Kabesch; C Hoefler; David Carr; W Leupold; Stephan K. Weiland; E. von Mutius

Background: It has been suggested that the genetically determined deficiency of glutathione S transferase (GST) enzymes involved in the detoxification of environmental tobacco smoke (ETS) components may contribute to the development of asthma. Methods: A large population of German schoolchildren (n = 3054) was genotyped for deficiencies of the GST isoforms M1 and T1. The association between GSTM1 and GSTT1 genotypes and asthma as well as atopy was investigated with respect to current and in utero ETS exposure. Results: In children lacking the GSTM1 allele who were exposed to current ETS the risk for current asthma (OR 5.5, 95% CI 1.6 to 18.6) and asthma symptoms such as wheeze ever (OR 2.8, 95% CI 1.3 to 6.0), current wheezing (OR 4.7, 95% CI 1.8 to 12.6) and shortness of breath (OR 8.9, 95% CI 2.1 to 38.4) was higher than in GSTM1 positive individuals without ETS exposure. Hints of an interaction between ETS exposure and GSTM1 deficiency were identified. In utero smoke exposure in GSTT1 deficient children was associated with significant decrements in lung function compared with GSTT1 positive children not exposed to ETS. Conclusions: GSTM1 and GSTT1 deficiency may increase the adverse health effects of in utero and current smoke exposure.


The Journal of Allergy and Clinical Immunology | 2010

A Genome-Wide Association Study on African-Ancestry Populations For Asthma

Rasika A. Mathias; Audrey V. Grant; Nicholas Rafaels; Tracey Hand; Li Gao; Candelaria Vergara; Yuhjung J. Tsai; Mao Yang; Monica Campbell; Cassandra Foster; Peisong Gao; Alkis Togias; Nadia N. Hansel; Gregory B. Diette; N. Franklin Adkinson; Mark C. Liu; Mezbah U. Faruque; Georgia M. Dunston; Harold Watson; Michael B. Bracken; Josephine Hoh; Pissamai Maul; Trevor Maul; Anne E. Jedlicka; Tanda Murray; Jacqueline B. Hetmanski; Roxann Ashworth; Chrissie M. Ongaco; Kurt N. Hetrick; Kimberly F. Doheny

BACKGROUND Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. OBJECTIVES We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma. METHODS We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. RESULTS A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. CONCLUSIONS This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.


European Journal of Human Genetics | 2008

Investigation of the fine structure of European populations with applications to disease association studies

Simon Heath; Ivo Gut; Paul Brennan; James D. McKay; Vladimir Bencko; Eleonora Fabianova; Lenka Foretova; Michael Georges; Vladimir Janout; Michael Kabesch; Hans E. Krokan; Maiken Bratt Elvestad; Jolanta Lissowska; Dana Mates; Peter Rudnai; Frank Skorpen; Stefan Schreiber; José Manuel Soria; Ann-Christine Syvänen; Pierre Meneton; Serge Hercberg; Pilar Galan; Neonilia Szeszenia-Dabrowska; David Zaridze; Emmanuel Génin; Lon R. Cardon; Mark Lathrop

An investigation into fine-scale European population structure was carried out using high-density genetic variation on nearly 6000 individuals originating from across Europe. The individuals were collected as control samples and were genotyped with more than 300 000 SNPs in genome-wide association studies using the Illumina Infinium platform. A major East–West gradient from Russian (Moscow) samples to Spanish samples was identified as the first principal component (PC) of the genetic diversity. The second PC identified a North–South gradient from Norway and Sweden to Romania and Spain. Variation of frequencies at markers in three separate genomic regions, surrounding LCT, HLA and HERC2, were strongly associated with this gradient. The next 18 PCs also accounted for a significant proportion of genetic diversity observed in the sample. We present a method to predict the ethnic origin of samples by comparing the sample genotypes with those from a reference set of samples of known origin. These predictions can be performed using just summary information on the known samples, and individual genotype data are not required. We discuss issues raised by these data and analyses for association studies including the matching of case-only cohorts to appropriate pre-collected control samples for genome-wide association studies.


The Journal of Allergy and Clinical Immunology | 2008

Toll-like receptor heterodimer variants protect from childhood asthma

Michael Kormann; Martin Depner; Dominik Hartl; Norman Klopp; Thomas Illig; Jerzy Adamski; Christian Vogelberg; Stephan K. Weiland; Erika von Mutius; Michael Kabesch

BACKGROUND Early exposure to microbes reduces the risk for asthma. Toll-like receptors (TLRs) represent a major group of receptors for the specific recognition of pathogen-associated molecular patterns of microbes capable of activating innate and adaptive immunity. OBJECTIVE Because TLRs can influence key events in the induction and perpetuation of asthma and atopy, we sought to determine whether genetic alterations in TLR genes affect asthma risk. METHODS We systematically evaluated putatively functional genetic variants in all 10 human TLR genes for their association with different asthma phenotypes in a case-control study (n = 1872) by using matrix-assisted laser desorption/ionization time-of-flight genotyping. For polymorphisms showing association with atopic asthma, effects on gene and protein expression were studied by means of RT-PCR and flow cytometry ex vivo. T-cell cytokine production was evaluated by means of ELISA after stimulation of the respective TLRs with specific ligands. RESULTS Protective effects on atopic asthma were identified for single nucleotide polymorphisms in TLR1 (odds ratio [OR], 0.54; 95% CI, 0.37-0.81; P = .002), TLR6 (OR, 0.54; 95% CI, 0.37-0.79; P = .003), and TLR10 (OR, 0.58; 95% CI, 0.39-0.86; P = .006), all capable of forming heterodimers with TLR2. Effects remained significant after correction for multiple comparisons. PBMCs of minor allele carriers showed increased levels of the respective TLR mRNA and proteins, augmented inflammatory responses, increased T(H)1 cytokine expression, and reduced T(H)2-associated IL-4 production after specific stimulation. CONCLUSION These results suggest that functional relevant TLR1 and TLR6 variants are directly involved in asthma development.


Nature Genetics | 2013

High-density genotyping study identifies four new susceptibility loci for atopic dermatitis.

David Ellinghaus; Hansjörg Baurecht; Elke Rodriguez; Anja Matanovic; Ingo Marenholz; Norbert Hubner; Heidi Schaarschmidt; Natalija Novak; Sven Michel; Laura Maintz; Thomas Werfel; Ulf Meyer-Hoffert; Melanie Hotze; Holger Prokisch; Katharina Heim; Christian Herder; Tomomitsu Hirota; Mayumi Tamari; Michiaki Kubo; Atsushi Takahashi; Yusuke Nakamura; Lam C. Tsoi; Philip E. Stuart; James T. Elder; Liangdan Sun; Xianbo Zuo; Sen Yang; Xuejun Zhang; Per Hoffmann; Markus M. Nöthen

Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.

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Thomas Illig

Hannover Medical School

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Sven Michel

Boston Children's Hospital

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Norman Klopp

Hannover Medical School

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Christian Vogelberg

Dresden University of Technology

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Andrea Heinzmann

Boston Children's Hospital

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Josef Riedler

Boston Children's Hospital

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