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Daniel P Potaczek,
Sven Michel,
Vishwas Sharma,
Sonja Zeilinger,
Christian Vogelberg,
Andrea von Berg,
Albrecht Bufe, Andrea Heinzmann,
Otto Laub,
Ernst Rietschel,
Burkhard Simma,
Thomas Frischer,
Jon Genuneit,
Thomas Illig,
Michael Kabesch
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ABSTRACT: BACKGROUND: Recently, three genome-wide association studies (GWAS) demonstrated FCER1A, the gene encoding a ligand-binding subunit of the high-affinity IgE receptor, to be a major susceptibility locus for serum IgE levels. The top association signal differed between the two studies from the general population and the one based on an asthma case-control design. In this study, we investigated whether different FCER1A polymorphisms are associated with total serum IgE in the general population and asthmatics specifically. METHODS: Nineteen polymorphisms were studied in FCER1A based on a detailed literature search and a tagging approach. Polymorphisms were genotyped by the Illumina HumanHap300Chip (6 polymorphisms) or MALDI-TOF MS (13 polymorphisms) in at least 1303 children (651 asthmatics) derived from the German International Study of Asthma and Allergies in Childhood II and Multicentre Asthma Genetics in Childhood Study. RESULTS: Similar to two population-based GWAS, the peak association with total serum IgE was observed for SNPs rs2511211, rs2427837, and rs2251746 (mean r(2) > 0.8), with the lowest p-value of 4.37 × 10(-6) . The same 3 polymorphisms showed the strongest association in non-asthmatics (lowest p = 0.0003). While these polymorphisms were also associated with total serum IgE in asthmatics (lowest p = 0.003), additional polymorphisms (rs3845625, rs7522607, and rs2427829) demonstrated associations with total serum IgE in asthmatics only (lowest p = 0.01). CONCLUSIONS: These data suggest that FCER1A polymorphisms not only drive IgE levels in the general population but that specific polymorphisms may also influence IgE in association with asthma, suggesting that disease-specific mechanisms in IgE regulation exist.
Pediatric Allergy and Immunology 06/2013; · 2.46 Impact Factor
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Ramesh Chandra Pandey,
Sven Michel,
Maximilian Schieck,
Aristea Binia,
Liming Liang,
Norman Klopp,
Andre Franke,
Andrea von Berg,
Albrecht Bufe,
Ernst Rietschel, Andrea Heinzmann,
Otto Laub,
Burkhard Simma,
Thomas Frischer,
Jon Genuneit,
Thomas Illig,
Michael Kabesch
The Journal of allergy and clinical immunology 02/2013; · 9.17 Impact Factor
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Ramesh Chandra Pandey,
Sven Michel,
Riccardina Tesse,
Aristea Binia,
Michaela Schedel,
Liming Liang,
Norman Klopp,
Andre Franke,
Andrea von Berg,
Albrecht Bufe,
Ernst Rietschel, Andrea Heinzmann,
Otto Laub,
Burkhard Simma,
Thomas Frischer,
Jon Genuneit,
Thomas Illig,
Michael Kabesch
The Journal of allergy and clinical immunology 12/2012; · 9.17 Impact Factor
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ABSTRACT: While pleuropulmonary involvement in systemic lupus erythematosus (SLE) is a common occurrence, shrinking lung syndrome (SLS) is a rare complication of SLE, particularly in children. We report on a teenager girl with a primary SLE diagnosis, which was based upon clinical, imaging, lung-function and histological findings ascertained to be compatible with SLS. Following a pneumonia, the patient developed inflammatory residues in the lower lobes, an event that probably caused diaphragmatic immobility and subsequently led to SLS. Treatment response to steroids, cyclophosphamide and hydroxychloroquine in this case was excellent, and efficacy was more profound than previously has been reported in the literature with respect to pediatric patients. This case report argues that prognosis of SLS in SLE is likely to be favorable when the diagnosis is made early and the disease is treated appropriately. Pediatr Pulmonol. © 2012 Wiley Periodicals, Inc.
Pediatric Pulmonology 11/2012; · 2.53 Impact Factor
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Antoaneta A Toncheva,
Kathrin Suttner,
Sven Michel,
Norman Klopp,
Thomas Illig,
Tobias Balschun,
Christian Vogelberg,
Andrea von Berg,
Albrecht Bufe, Andrea Heinzmann,
Otto Laub,
Ernst Rietschel,
Burkhard Simma,
Thomas Frischer,
Jon Genuneit,
Erika von Mutius,
Michael Kabesch
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ABSTRACT: To cite this article: Toncheva AA, Suttner K, Michel S, Klopp N, Illig T, Balschun T, Vogelberg C, von Berg A, Bufe A, Heinzmann A, Laub O, Rietschel E, Simma B, Frischer T, Genuneit J, von Mutius E, Kabesch M. Genetic variants in Protocadherin-1, bronchial hyper-responsiveness, and asthma subphenotypes in German children. Pediatr Allergy Immunol 2012. ABSTRACT: Background: Recently, Protocadherin-1 (PCDH1) was reported as a novel susceptibility gene for bronchial hyper-responsiveness (BHR) and asthma. PCDH1 is located on chromosome 5q31-33, in the vicinity of several known candidate genes for asthma and allergy. To exclude that the associations observed for PCDH1 originate from the nearby cytokine cluster, an extensive linkage disequilibrium (LD) analysis was performed. Effects of polymorphisms in PCDH1 on asthma, BHR, and related phenotypes were studied comprehensively. Methods: Genotype information was acquired from Illumina HumanHap300Chip genotyping, MALDI-TOF MS genotyping, and imputation. LD was assessed by Haploview 4.2 software. Associations were investigated in a population of 1454 individuals (763 asthmatics) from two German study populations [MAGICS and International Study of Asthma and Allergies in Childhood phase II (ISAAC II)] using logistic regression to model additive effects. Results: No relevant LD between PCDH1 tagging polymorphisms and 98 single nucleotide polymorphisms within the cytokine cluster was detected. While BHR was not associated with PCDH1 polymorphisms, significant associations with subphenotypes of asthma were observed. Conclusion: Protocadherin-1 polymorphisms may specifically affect the development of non-atopic asthma in children. Functional studies are needed to further investigate the role of PCDH1 in BHR and asthma development.
Pediatric Allergy and Immunology 10/2012; · 2.46 Impact Factor
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Dara G Torgerson,
Elizabeth J Ampleford,
Grace Y Chiu,
W James Gauderman,
Christopher R Gignoux,
Penelope E Graves,
Blanca E Himes,
Albert M Levin,
Rasika A Mathias,
Dana B Hancock, [......],
Deborah A Meyers,
Stephanie J London,
Frank D Gilliland,
Esteban G Burchard,
Fernando D Martinez,
Scott T Weiss,
L Keoki Williams,
Kathleen C Barnes,
Carole Ober,
Dan L Nicolae
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ABSTRACT: Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
Nature Genetics 07/2011; 43(9):887-92. · 35.53 Impact Factor
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ABSTRACT: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is elevated in the airways of subjects with asthma and has been linked to the development of allergic airway disease by promoting STAT6-dependent T helper 2 cell (T(H) 2) effector functions. To determine whether single nucleotide polymorphisms (SNPs) in the TNFSF10 gene are associated with bronchial asthma we genotyped 498 Caucasian subjects living in Southern Germany for eight SNPs in the TNFSF10 by restriction fragment length polymorphism analysis. In contrast to single SNPs, haplotypes constructed from eight SNPs were robustly associated with asthma (p=0.00012). A small haplotype approach returned four alleles consisting of two (rs3136586/ rs3136598), three (rs12488654/rs3136586/rs3136598 and rs3136586/rs3136598/rs3136604), and four SNPs (rs12488654/ rs3136586/ rs3136598/ rs3136604) that were highly associated with asthma (p=0.00005, p=0.00008, p=0.00017 and p=0.00038). Combinations of SNPs in the TNFSF10 allele were strongly associated with asthma supporting the concept that TRAIL is important in the development of hallmark features of this disease.
Pediatric Allergy and Immunology 10/2010; 22(1 Pt 1):25-30. · 2.46 Impact Factor
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Charlotte M Niemeyer,
Michelle W Kang,
Danielle H Shin,
Ingrid Furlan,
Miriam Erlacher,
Nancy J Bunin,
Severa Bunda,
Jerry Z Finklestein,
Kathleen M Sakamoto,
Thomas A Gorr, [......],
Franco Locatelli,
Debbie Sakai,
Sophie Archambeault,
Leslie Chen,
Ryan C Russell,
Stephanie S Sybingco,
Michael Ohh,
Benjamin S Braun,
Christian Flotho,
Mignon L Loh
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ABSTRACT: CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.
Nature Genetics 09/2010; 42(9):794-800. · 35.53 Impact Factor
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Eva Halapi,
Daniel F Gudbjartsson,
Gudrun M Jonsdottir,
Unnur S Bjornsdottir,
Gudmar Thorleifsson,
Hafdis Helgadottir,
Carolyn Williams,
Gerard H Koppelman, Andrea Heinzmann,
H Marike Boezen, [......],
Klaus Deichmann,
Philip J Thompson,
Matthias Wjst,
Ian P Hall,
Dirkje S Postma,
Thorarinn Gislason,
Augustine Kong,
Ingileif Jonsdottir,
Unnur Thorsteinsdottir,
Kari Stefansson
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ABSTRACT: A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR=1.51, P=6.89.10(-9)) and adolescence (age: 14-17 years OR=1.71, P=5.47.10(-9)). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.
European journal of human genetics: EJHG 04/2010; 18(8):902-8. · 3.56 Impact Factor
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ABSTRACT: In the genetics of asthma, single genetic polymorphisms confer only a small individual risk factor. Haplotype-based association analyses, including joint analyses of several candidate genes, might therefore yield more convincing results than single-region statistics. We set out to test for joint influences of asthma genes previously identified in our study population that is acidic mammalian chitinase (AMCase), Toll-like receptor (TLR)-10, and the interleukins IL-4, IL-13, IL-8, and IL-15. In particular, we investigated whether haplotypes at two or three genes show stronger association with the trait than at a single gene alone. We genotyped 26 polymorphisms in 321 asthmatic children and 270 controls. Haplotype-based association analyses were performed by the program FAMHAP. Single-, two-, and three-gene analyses were conducted as well as conditional analyses for pairs of genes. In the two-region analyses, best evidence was found for a joint effect on asthma for AMCase and IL-4 (p(raw) < 5 x 10(-7)) as well as AMCase and IL-13 (p(raw) = 5 x 10(-7)). Besides, IL-13 and TLR-10 showed a stronger two-gene result (p(raw) = 0.001607) than the respective single-gene analyses. Conditional analyses yielded similar results for these two-gene combinations and also revealed mutual additional effects for IL-13 and IL-4 (p(stratified) = 0.014831 and 0.001525, respectively). The most significant results demonstrate a joint effect of AMCase with IL-4 or IL-13 on the trait. Furthermore, additional mutual effects were seen for AMCase and IL-4 as well as for TLR-10 and IL-13. The corresponding pathways might therefore be of particular importance in the genetics of asthma. Further studies are needed to elucidate the functional importance of these gene-gene effects and their precise role in asthma pathogenesis.
Pediatric Allergy and Immunology 04/2010; 21(4 Pt 2):e679-86. · 2.46 Impact Factor
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ABSTRACT: Bronchopulmonary dysplasia (BPD) is the chronic lung disease of preterm infants and still represents a major burden of prematurity. Several clinical risk factors for the onset of the disease are already known. In addition, some candidate genes have recently been identified. We set out to determine clinical as well as genetic risk factors for the development of BPD in the German population. 155 infants born with a gestational age < or = 28 at the tertiary neonatal Centre, Freiburg, were recruited. Clinical data were recorded from hospital charts. 47 children developed moderate or severe BPD. For genetic analyses, 37 polymorphisms within sixteen genes were genotyped on all children. The strongest epidemiological risk factor for BPD was birth weight, followed by low gestational age. Genetic association was detected with single polymorphisms within Tumour necrosis factor alpha, Toll like receptor 10 and vascular endothelial growth factor. The former two genes showed also association with BPD in haplotype analyses. In conclusion, association of BPD was far more convincingly found with a few clinical factors than with genetic polymorphisms. This underscores the genetic complexity of the disease. Furthermore, the identification of predisposing genetic polymorphisms might be hampered by the complex interaction between clinical and genetic factors.
Disease markers 01/2010; 29(1):1-9. · 1.64 Impact Factor
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Sven Michel,
Liming Liang,
Martin Depner,
Norman Klopp,
Andreas Ruether,
Ashish Kumar,
Michaela Schedel,
Christian Vogelberg,
Erika von Mutius,
Andrea von Berg, [......], Andrea Heinzmann,
Otto Laub,
Burkhard Simma,
Thomas Frischer,
Jon Genuneit,
Ivo G Gut,
Stefan Schreiber,
Mark Lathrop,
Thomas Illig,
Michael Kabesch
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ABSTRACT: The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values <0.0035 (corrected for multiple testing). Combining genotyping and imputation, polymorphisms in DPP10, EDN1, IL12B, IL13, IL4, IL4R and TNF showed associations at a significance level between p = 0.05 and p = 0.0035. These data indicate that (a) GWAS coverage is insufficient for many asthma candidate genes, (b) imputation based on these data is reliable but incomplete, and (c) SNPs in three previously identified asthma candidate genes replicate in our GWAS population with significance after correction for multiple testing in 14 genes.
PLoS ONE 01/2010; 5(11):e13894. · 4.09 Impact Factor
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James M Stark,
M Michael Barmada,
Abby V Winterberg,
Nilanjana Majumber,
William J Gibbons,
Marilyn A Stark,
Maureen A Sartor,
Mario Medvedovic,
Jay Kolls,
Kiflai Bein,
Beena Mailaparambil,
Marcus Krueger, Andrea Heinzmann,
George D Leikauf,
Daniel R Prows
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ABSTRACT: Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in infants, with about half being infected in their first year of life. Yet only 2 to 3% of infants are hospitalized for RSV infection, suggesting that individual susceptibility contributes to disease severity. Previously, we determined that AKR/J (susceptible) mice developed high lung RSV titers and showed delayed weight recovery, whereas C57BL/6J (resistant) mice demonstrated low lung RSV titers and rapid weight recovery. In addition, we have reported that gene-targeted mice lacking the cystic fibrosis transmembrane conductance regulator (Cftr; ATP-binding cassette subfamily C, member 7) are susceptible to RSV infection. For this report, recombinant backcross and F2 progeny derived from C57BL/6J and AKR/J mice were infected with RSV, their lung titers were measured, and quantitative trait locus (QTL) analysis was performed. A major QTL, designated Rsvs1, was identified on proximal mouse chromosome 6 in both recombinant populations. Microarray analysis comparing lung transcripts of the parental strains during infection identified several candidate genes that mapped to the Rsvs1 interval, including Cftr. These findings add to our understanding of individual RSV susceptibility and strongly support a modifier role for CFTR in RSV infection, a significant cause of respiratory morbidity in infants with cystic fibrosis.
Journal of Virology 12/2009; 84(5):2257-69. · 5.40 Impact Factor
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ABSTRACT: Infection with respiratory syncytial virus (RSV) is a leading cause of upper and lower respiratory tract infection in infants. It is accompanied by a considerably disease burden and a hospitalisation rate of up to 3% in infected infants. Besides, it is still a matter of intensive discussion whether severe RSV infection in early infancy causes the development of asthma later in live or whether RSV bronchiolitis just chronologically precedes asthma in children who are susceptible to asthma. The latter could be due to a common genetic background of both diseases predisposing to an exaggerated inflammatory response of the lungs to allergens and pathogens. Genetic studies might help to elucidate the mechanisms leading to both diseases and to highlight common as well as diverse pathways. The results of such investigations will influence the current understanding of the diseases and might even change our therapeutical approaches to both disorders. This review summarizes current findings in the genetics of bronchial asthma and severe RSV bronchiolitis. The question whether a relationship exists between severe RSV bronchiolitis in infancy and childhood asthma will also be discussed by taking recent epidemiological studies in account. A special focus is laid on the implications of these findings for a targeted drug therapy of both diseases.
Inflammation & allergy drug targets. 08/2009; 8(3):202-7.
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ABSTRACT: Preterm birth (PTB) is accompanied by an increased neonatal morbidity. The cause of PTB is multifactorial and the interplay between environmental and genetic factors - of mothers and newborns - determines the risk.
We were interested to identify fetal genes predisposing to PTB in the German population.
We started our study by screening 31 polymorphisms within 15 genes of 121 preterm infants born below 32 gestational weeks and 270 healthy controls. Genotyping was performed by restriction fragment length polymorphism. Statistical analyses used Armitage's trend test for single polymorphisms and FAMHAP for calculation of haplotypes.
No single polymorphism showed association with PTB; however, haplotypes of interleukin (IL)-13/IL-4 and Toll-like receptor (TLR)-10 were associated (p = 0.0001 and p = 0.0011, respectively). The association was further confirmed in an extended population of a total of 164 preterm infants. Furthermore, one polymorphism in IL-13 showed a weak association with PTB in this population (p = 0.031). Finally, we analyzed whether the cause of PTB, i.e. medically indicated cesarean section versus spontaneous PTB, affects association results and found evidence in favor of a separate analysis of both groups.
IL-13/IL-4 and TLR-10 might be involved in the genetics of PTB. The dissection of the genetic background may provide a deeper understanding of the pathophysiology of PTB and help to identify new drug targets for its prevention.
Neonatology 04/2009; 96(3):175-81. · 2.66 Impact Factor
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Daniel F Gudbjartsson,
Unnur S Bjornsdottir,
Eva Halapi,
Anna Helgadottir,
Patrick Sulem,
Gudrun M Jonsdottir,
Gudmar Thorleifsson,
Hafdis Helgadottir,
Valgerdur Steinthorsdottir,
Hreinn Stefansson, [......],
Philip J Thompson,
Matthias Wjst,
Ian P Hall,
Dirkje S Postma,
Thorarinn Gislason,
Jeffrey Gulcher,
Augustine Kong,
Ingileif Jonsdottir,
Unnur Thorsteinsdottir,
Kari Stefansson
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ABSTRACT: Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).
Nature Genetics 03/2009; 41(3):342-7. · 35.53 Impact Factor
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ABSTRACT: The incidence of caesarean section (CS) is steadily rising world-wide. In particular, CS on maternal demand is performed more frequently. In parts, this might be due to insufficient information of pregnant women about neonatal risks of CS. We sought to specify neonatal outcomes following different modes of delivery, i.e. vaginal delivery, primary CS and secondary CS and to define risk factors for respiratory morbidity and hospitalization.
We analysed 2073 births (gestational age > 35 weeks) during a two-year period at a tertiary obstetric and neonatal centre in Germany. Statistical analyses were performed for single parameters by SPSS as well as by logistic regression to account for possible confounders. Furthermore, extensive model calculation was done.
Respiratory morbidity was increased following primary and secondary CS (p = 0.001). By multiple logistic regression, the strongest effect on respiratory symptoms was seen with gestational age, each week more in utero reducing the risk by an odds ratio (OR) of 0.69 (95% CI: [0.61; 0.79]; p = 1.9 x 10(-8)). Furthermore, a significant interaction between mode of delivery and gestational age was found for the risk of respiratory symptoms (p = 0.0035).
For every eight newborns delivered by primary CS one more than expected with vaginal delivery is hospitalized. It is highly relevant to recognize that each week of gestational age reduces the risk of respiratory symptoms, especially if primary CS is performed. The higher rate of respiratory morbidity and neonatal admission following CS should be clearly recognized in counselling of pregnant women.
Acta Paediatrica 01/2009; 98(1):25-30. · 2.07 Impact Factor
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ABSTRACT: Because of their important role in the pathophysiology of severe RSV infection, IFNs represent an ideal group of candidate genes for determining RSV disease severity. We studied 14 polymorphisms within 7 genes involved in IFNs signalling. Our study populations consisted of 156 infants with severe RSV infection and 296 healthy control children. None of the genes showed association with severe RSV infection in children. Thus, despite the involvement of different IFNs in the pathophysiology of RSV infection, genetic variants in IFNG and related genes might not alter the risk for the development of severe RSV-associated diseases.
Archives of Virology 11/2008; 153(11):2133-7. · 2.11 Impact Factor
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ABSTRACT: Tumor necrosis factor (TNF-) is a proinflammatory cytokine that is important in the innate host defence and thus in the defence of infectious agents. However, in excess it provokes the development of chronic inflammatory diseases. The aim of this study was to test association of TNF with severe RSV bronchiolitis as example of an infectious disease and asthma as representative for a chronic inflammatory condition. The following study populations were genotyped for 4 polymorphisms within TNF-β (rs909253) and TNF- (rs1799964, rs1799724, rs1800629): 322 asthmatic children, 151 children with severe respiratory syncytial virus (RSV) bronchiolitis and 270 controls. Furthermore, serum TNF- levels were measured by a FlowCytomix Assay. Asthma showed association with two TNF- polymorphisms as well as with TNF haplotpyes (p = 0.0050). In contrast, RSV bronchiolitis was associated with TNF haplotypes (p < 0.00001) but not with any single polymorphism. In addition, TNF- serum levels correlated with rs1799724 (p = 0.034). A genetically mediated up-regulation of TNF- expression might provoke a pronounced inflammation of the airways and thus a more severe course of RSV infection as well as the onset of asthma. It remains to be elucidated whether severe RSV bronchiolitis starts TNF- upregulation and is one first step in the direction to asthma later in life, or whether both dieases are independent from each other and supported by TNF- upregulation.
Pediatric Allergy and Immunology 09/2008; 20(2):157 - 163. · 2.46 Impact Factor
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ABSTRACT: Tumor necrosis factor (TNF-)alpha is a proinflammatory cytokine that is important in the innate host defence and thus in the defence of infectious agents. However, in excess it provokes the development of chronic inflammatory diseases. The aim of this study was to test association of TNF with severe RSV bronchiolitis as example of an infectious disease and asthma as representative for a chronic inflammatory condition. The following study populations were genotyped for 4 polymorphisms within TNF-beta (rs909253) and TNF-alpha (rs1799964, rs1799724, rs1800629): 322 asthmatic children, 151 children with severe respiratory syncytial virus (RSV) bronchiolitis and 270 controls. Furthermore, serum TNF-alpha levels were measured by a FlowCytomix Assay. Asthma showed association with two TNF-alpha polymorphisms as well as with TNF haplotypes (p = 0.0050). In contrast, RSV bronchiolitis was associated with TNF haplotypes (p < 0.00001) but not with any single polymorphism. In addition, TNF-alpha serum levels correlated with rs1799724 (p = 0.034). A genetically mediated up-regulation of TNF-alpha expression might provoke a pronounced inflammation of the airways and thus a more severe course of RSV infection as well as the onset of asthma. It remains to be elucidated whether severe RSV bronchiolitis starts TNF-alpha upregulation and is one first step in the direction to asthma later in life, or whether both diseases are independent from each other and supported by TNF-alpha upregulation.
Pediatric Allergy and Immunology 09/2008; 20(2):157-63. · 2.46 Impact Factor
