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1. Effects of an exclusive human-milk diet in preterm neonates on early vascular aging risk factors (NEOVASC): study protocol for a multicentric, prospective, randomized, controlled, open, and parallel group clinical trial.

Author

Mitterer, Wolfgang, Mitterer, Wolfgang, Binder, Christoph, Blassnig-Ezeh, Anya, Auer-Hackenberg, Lorenz, Berger, Angelika, Simma, Burkhard, Wald, Martin, Lee, Martin, Kiechl-Kohlendorfer, Ursula, Mitterer, Wolfgang, Mitterer, Wolfgang, Binder, Christoph, Blassnig-Ezeh, Anya, Auer-Hackenberg, Lorenz, Berger, Angelika, Simma, Burkhard, Wald, Martin, Lee, Martin, and Kiechl-Kohlendorfer, Ursula

Abstract

BackgroundPreterm birth accounts for approximately 11% of all livebirths globally. Due to improvements in perinatal care, more than 95% of these infants now survive into adulthood. Research has indicated a robust association between prematurity and increased cardiovascular risk factors and cardiovascular mortality. While the innate adverse effects of prematurity on these outcomes have been demonstrated, therapeutic strategies on the mitigation of these concerning developments are lacking. The primary objective of the NEOVASC clinical trial is therefore to investigate whether the administration of a prolonged exclusive human-milk diet in preterm infants is capable of alleviating the harmful effects of preterm birth on the early development of cardiovascular risk factors.MethodsThe NEOVASC study is a multicentric, prospective, randomized, controlled, open, and parallel group clinical trial conducted in four Austrian tertiary neonatal care facilities. The purpose of the present trial is to investigate the effects of a prolonged exclusive human-milk-diet devoid of bovine-milk-based food components on cardiovascular and metabolic risk factors at 1, 2, and 5 years of corrected age. Primary outcomes include assessments of fasting blood glucose levels, blood pressure levels, and the distensibility of the descending aorta using validated echocardiographic protocols at 5 years of corrected age. The test group, which consists of 200 preterm infants, will therefore be compared to a control group of 100 term-born infants and a historical control group recruited previously.DiscussionGiven the emerging implications of an increased cardiovascular risk profile in the potentially growing population of preterm infants, further research on the mitigation of long-term morbidities in formerly preterm infants is urgently warranted. Further optimizing preterm infants' nutrition by removing bovine-milk-based food components may therefore be an interesting approach worth pursuing.Trial regis

Published
2021

2. Nocturnal asthma is affected by genetic interactions between RORA and NPSR1

Author

Gaertner, Vincent D., Michel, Sven, Curtin, John A., Pulkkinen, Ville, Acevedo, Nathalie, Soderhall, Cilla, von Berg, Andrea, Bufe, Albrecht, Laub, Otto, Rietschel, Ernst, Heinzmann, Andrea, Simma, Burkhard, Vogelberg, Christian, Pershagen, Goeran, Melen, Erik, Simpson, Angela, Custovic, Adnan, Kere, Juha, Kabesch, Michael, Gaertner, Vincent D., Michel, Sven, Curtin, John A., Pulkkinen, Ville, Acevedo, Nathalie, Soderhall, Cilla, von Berg, Andrea, Bufe, Albrecht, Laub, Otto, Rietschel, Ernst, Heinzmann, Andrea, Simma, Burkhard, Vogelberg, Christian, Pershagen, Goeran, Melen, Erik, Simpson, Angela, Custovic, Adnan, Kere, Juha, and Kabesch, Michael

Abstract

BackgroundNeuropeptide S Receptor 1 (NPSR1) and Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA ) interact biologically, are both known candidate genes for asthma, and are involved in controlling circadian rhythm. Thus, we assessed (1) whether interactions between RORA and NPSR1 specifically affect the nocturnal asthma phenotype and (2) how this may differ from other asthma phenotypes. MethodsInteraction effects between 24 single-nucleotide polymorphisms (SNPs) in RORA and 35 SNPs in NPSR1 on asthma and nocturnal asthma symptoms were determined in 1432 subjects (763 asthmatics [192 with nocturnal asthma symptoms]; 669 controls) from the Multicenter Asthma Genetic in Childhood/International Study of Asthma and Allergies in Childhood studies. The results were validated and extended in children from the Manchester Asthma and Allergy Study (N=723) and the Children Allergy Milieu Stockholm and Epidemiological cohort (N=1646). ResultsRORA*NPSR1 interactions seemed to affect both asthma and nocturnal asthma. In stratified analyses, however, interactions mainly affected nocturnal asthma and less so asthma without nocturnal symptoms or asthma severity. Results were replicated in two independent cohorts and seemed to remain constant over time throughout youth. ConclusionRORA*NPSR1 interactions appear to be involved in mechanisms specific for nocturnal asthma. In contrast to previous studies focusing on the role of beta 2 receptor polymorphisms in nocturnal asthma as a feature of asthma control or severity in general, our data suggest that changes in circadian rhythm control are associated with nighttime asthma symptoms.

Published
2019

3. Nocturnal asthma is affected by genetic interactions between RORA and NPSR1

Author

Gaertner, Vincent D., Michel, Sven, Curtin, John A., Pulkkinen, Ville, Acevedo, Nathalie, Soderhall, Cilla, von Berg, Andrea, Bufe, Albrecht, Laub, Otto, Rietschel, Ernst, Heinzmann, Andrea, Simma, Burkhard, Vogelberg, Christian, Pershagen, Goeran, Melen, Erik, Simpson, Angela, Custovic, Adnan, Kere, Juha, Kabesch, Michael, Gaertner, Vincent D., Michel, Sven, Curtin, John A., Pulkkinen, Ville, Acevedo, Nathalie, Soderhall, Cilla, von Berg, Andrea, Bufe, Albrecht, Laub, Otto, Rietschel, Ernst, Heinzmann, Andrea, Simma, Burkhard, Vogelberg, Christian, Pershagen, Goeran, Melen, Erik, Simpson, Angela, Custovic, Adnan, Kere, Juha, and Kabesch, Michael

Abstract

BackgroundNeuropeptide S Receptor 1 (NPSR1) and Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA ) interact biologically, are both known candidate genes for asthma, and are involved in controlling circadian rhythm. Thus, we assessed (1) whether interactions between RORA and NPSR1 specifically affect the nocturnal asthma phenotype and (2) how this may differ from other asthma phenotypes. MethodsInteraction effects between 24 single-nucleotide polymorphisms (SNPs) in RORA and 35 SNPs in NPSR1 on asthma and nocturnal asthma symptoms were determined in 1432 subjects (763 asthmatics [192 with nocturnal asthma symptoms]; 669 controls) from the Multicenter Asthma Genetic in Childhood/International Study of Asthma and Allergies in Childhood studies. The results were validated and extended in children from the Manchester Asthma and Allergy Study (N=723) and the Children Allergy Milieu Stockholm and Epidemiological cohort (N=1646). ResultsRORA*NPSR1 interactions seemed to affect both asthma and nocturnal asthma. In stratified analyses, however, interactions mainly affected nocturnal asthma and less so asthma without nocturnal symptoms or asthma severity. Results were replicated in two independent cohorts and seemed to remain constant over time throughout youth. ConclusionRORA*NPSR1 interactions appear to be involved in mechanisms specific for nocturnal asthma. In contrast to previous studies focusing on the role of beta 2 receptor polymorphisms in nocturnal asthma as a feature of asthma control or severity in general, our data suggest that changes in circadian rhythm control are associated with nighttime asthma symptoms.

Published
2019

4. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages

Author

Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, Kabesch, Michael, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, and Kabesch, Michael

Published
2016

5. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages

Author

Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, Kabesch, Michael, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, and Kabesch, Michael

Published
2016

6. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages

Author

dIRAS RA-2, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, Kabesch, Michael, dIRAS RA-2, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, and Kabesch, Michael

Published
2016

7. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages

Author

Schieck, Maximilian, Schouten, Jan P., Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A., Gaertner, Vincent D., Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M., Birben, Esra, Melen, Erik, Pershagen, Goeran, Freidin, Maxim B., Ogorodova, Ludmila M., Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriette A., Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S., Koppelman, Gerard H., Vonk, Judith M., Timens, Wim, Boezen, H. Marike, Kabesch, Michael, Schieck, Maximilian, Schouten, Jan P., Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A., Gaertner, Vincent D., Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M., Birben, Esra, Melen, Erik, Pershagen, Goeran, Freidin, Maxim B., Ogorodova, Ludmila M., Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriette A., Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S., Koppelman, Gerard H., Vonk, Judith M., Timens, Wim, Boezen, H. Marike, and Kabesch, Michael

Abstract

Background: Asthma is a disease affecting more boys than girls in childhood and more women than men in adulthood. The mechanisms behind these sex-specific differences are not yet understood. Objective: We analyzed whether and how genetic factors contribute to sex-specific predispositionto childhood-onset asthma. Methods: Interactions between sex and polymorphisms on childhood asthma risk were evaluated in the Multicentre Asthma Genetics in Childhood Study (MAGICS)/Phase II International Study of Asthma and Allergies in Childhood (ISAAC II) population on a genome-wide level, and findings were validated in independent populations. Genetic fine mapping of sex-specific asthma association signals was performed, and putatively causal polymorphisms were characterized in vitro by using electrophoretic mobility shift and luciferase activity assays. Gene and protein expression of the identified gene doublesex and mab-3 related transcription factor 1 (DMRT1) were measured in different human tissues by using quantitative real-time PCR and immunohistochemistry. Results: Polymorphisms in the testis-associated gene DMRT1 displayed interactions with sex on asthma status in a population of primarily clinically defined asthmatic children and nonasthmatic control subjects (lowest P = 5.21 x 10(-6)). Replication of this interaction was successful in 2 childhood populations clinically assessed for asthma but showed heterogeneous results in other population-based samples. Polymorphism rs3812523 located in the putative DMRT1 promoter was associated with allele-specific changes in transcription factor binding and promoter activity in vitro. DMRT1 expression was observed not only in the testis but also in lung macrophages. Conclusion: DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation.

Published
2016

8. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages

Author

Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, Kabesch, Michael, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, and Kabesch, Michael

Published
2016

9. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages

Author

dIRAS RA-2, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, Kabesch, Michael, dIRAS RA-2, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, and Kabesch, Michael

Published
2016

10. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages

Author

Epi Infectieziekten Team 3, Infection & Immunity, Circulatory Health, JC onderzoeksprogramma Infectieziekten, Cardiometabolic Health, Child Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, Kabesch, Michael, Epi Infectieziekten Team 3, Infection & Immunity, Circulatory Health, JC onderzoeksprogramma Infectieziekten, Cardiometabolic Health, Child Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, and Kabesch, Michael

Published
2016

11. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages

Author

dIRAS RA-2, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, Kabesch, Michael, dIRAS RA-2, Schieck, Maximilian, Schouten, Jan P, Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A, Gaertner, Vincent D, Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M, Birben, Esra, Melén, Erik, Pershagen, Göran, Freidin, Maxim B, Ogorodova, Ludmila M, Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriëtte A, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S, Koppelman, Gerard H, Vonk, Judith M, Timens, Wim, Boezen, H Marike, and Kabesch, Michael

Published
2016

12. Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages

Author

Schieck, Maximilian, Schouten, Jan P., Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A., Gaertner, Vincent D., Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M., Birben, Esra, Melen, Erik, Pershagen, Goeran, Freidin, Maxim B., Ogorodova, Ludmila M., Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriette A., Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S., Koppelman, Gerard H., Vonk, Judith M., Timens, Wim, Boezen, H. Marike, Kabesch, Michael, Schieck, Maximilian, Schouten, Jan P., Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A., Gaertner, Vincent D., Illig, Thomas, Lipinski, Simone, Franke, Andre, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M., Birben, Esra, Melen, Erik, Pershagen, Goeran, Freidin, Maxim B., Ogorodova, Ludmila M., Granell, Raquel, Henderson, John, Brunekreef, Bert, Smit, Henriette A., Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S., Koppelman, Gerard H., Vonk, Judith M., Timens, Wim, Boezen, H. Marike, and Kabesch, Michael

Abstract

Background: Asthma is a disease affecting more boys than girls in childhood and more women than men in adulthood. The mechanisms behind these sex-specific differences are not yet understood. Objective: We analyzed whether and how genetic factors contribute to sex-specific predispositionto childhood-onset asthma. Methods: Interactions between sex and polymorphisms on childhood asthma risk were evaluated in the Multicentre Asthma Genetics in Childhood Study (MAGICS)/Phase II International Study of Asthma and Allergies in Childhood (ISAAC II) population on a genome-wide level, and findings were validated in independent populations. Genetic fine mapping of sex-specific asthma association signals was performed, and putatively causal polymorphisms were characterized in vitro by using electrophoretic mobility shift and luciferase activity assays. Gene and protein expression of the identified gene doublesex and mab-3 related transcription factor 1 (DMRT1) were measured in different human tissues by using quantitative real-time PCR and immunohistochemistry. Results: Polymorphisms in the testis-associated gene DMRT1 displayed interactions with sex on asthma status in a population of primarily clinically defined asthmatic children and nonasthmatic control subjects (lowest P = 5.21 x 10(-6)). Replication of this interaction was successful in 2 childhood populations clinically assessed for asthma but showed heterogeneous results in other population-based samples. Polymorphism rs3812523 located in the putative DMRT1 promoter was associated with allele-specific changes in transcription factor binding and promoter activity in vitro. DMRT1 expression was observed not only in the testis but also in lung macrophages. Conclusion: DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation.

Published
2016

13. Neonatal assessment in the delivery room – Trial to Evaluate a Specified Type of Apgar (TEST-Apgar)

Author

TEST-Apgar study-group, Rüdiger, Mario, Braun, Nicole, Aranda, Jacob, Aguar, Marta, Bergert, Renate, Bystricka, Alica, Dimitriou, Gabriel, El-Atawi, Khaled, Ifflaender, Sascha, Jung, Philipp, Matasova, Katarina, Ojinaga, Violeta, Petruskeviciene, Zita, Roll, Claudia, Schwindt, Jens, Simma, Burkhard, Staal, Nanette, Valencia, Gloria, Vasconcellos, Maria Gabriela, Veinla, Maie, Vento, Máximo, Weber, Benedikt, Wendt, Anke, Yigit, Sule, Zotter, Heinz, Küster, Helmut, TEST-Apgar study-group, Rüdiger, Mario, Braun, Nicole, Aranda, Jacob, Aguar, Marta, Bergert, Renate, Bystricka, Alica, Dimitriou, Gabriel, El-Atawi, Khaled, Ifflaender, Sascha, Jung, Philipp, Matasova, Katarina, Ojinaga, Violeta, Petruskeviciene, Zita, Roll, Claudia, Schwindt, Jens, Simma, Burkhard, Staal, Nanette, Valencia, Gloria, Vasconcellos, Maria Gabriela, Veinla, Maie, Vento, Máximo, Weber, Benedikt, Wendt, Anke, Yigit, Sule, Zotter, Heinz, and Küster, Helmut

Abstract

Background: Since an objective description is essential to determine infant’s postnatal condition and efficacy of interventions, two scores were suggested in the past but weren’t tested yet: The Specified-Apgar uses the 5 items of the conventional Apgar score; however describes the condition regardless of gestational age (GA) or resuscitative interventions. The Expanded-Apgar measures interventions needed to achieve this condition. We hypothesized that the combination of both (Combined-Apgar) describes postnatal condition of preterm infants better than either of the scores alone. Methods: Scores were assessed in preterm infants below 32 completed weeks of gestation. Data were prospectively collected in 20 NICU in 12 countries. Prediction of poor outcome (death, severe/moderate BPD, IVH, CPL and ROP) was used as a surrogate parameter to compare the scores. To compare predictive value the AUC for the ROC was calculated. Results: Of 2150 eligible newborns, data on 1855 infants with a mean GA of 286/7± 23/7 weeks were analyzed. At 1 minute, the Combined-Apgar was significantly better in predicting poor outcome than the Specified- or Expanded-Apgar alone. Of infants with a very low score at 5 or 10 minutes 81% or 100% had a poor outcome, respectively. In these infants the relative risk (RR) for perinatal mortality was 24.93 (13.16-47.20) and 31.34 (15.91-61.71), respectively. Conclusion: The Combined-Apgar allows a more appropriate description of infant’s condition under conditions of modern neonatal care. It should be used as a tool for better comparison of group of infants and postnatal interventions.

Published
2015

14. Neonatal assessment in the delivery room – Trial to Evaluate a Specified Type of Apgar (TEST-Apgar)

Author

TEST-Apgar study-group, Rüdiger, Mario, Braun, Nicole, Aranda, Jacob, Aguar, Marta, Bergert, Renate, Bystricka, Alica, Dimitriou, Gabriel, El-Atawi, Khaled, Ifflaender, Sascha, Jung, Philipp, Matasova, Katarina, Ojinaga, Violeta, Petruskeviciene, Zita, Roll, Claudia, Schwindt, Jens, Simma, Burkhard, Staal, Nanette, Valencia, Gloria, Vasconcellos, Maria Gabriela, Veinla, Maie, Vento, Máximo, Weber, Benedikt, Wendt, Anke, Yigit, Sule, Zotter, Heinz, Küster, Helmut, TEST-Apgar study-group, Rüdiger, Mario, Braun, Nicole, Aranda, Jacob, Aguar, Marta, Bergert, Renate, Bystricka, Alica, Dimitriou, Gabriel, El-Atawi, Khaled, Ifflaender, Sascha, Jung, Philipp, Matasova, Katarina, Ojinaga, Violeta, Petruskeviciene, Zita, Roll, Claudia, Schwindt, Jens, Simma, Burkhard, Staal, Nanette, Valencia, Gloria, Vasconcellos, Maria Gabriela, Veinla, Maie, Vento, Máximo, Weber, Benedikt, Wendt, Anke, Yigit, Sule, Zotter, Heinz, and Küster, Helmut

Abstract

Background: Since an objective description is essential to determine infant’s postnatal condition and efficacy of interventions, two scores were suggested in the past but weren’t tested yet: The Specified-Apgar uses the 5 items of the conventional Apgar score; however describes the condition regardless of gestational age (GA) or resuscitative interventions. The Expanded-Apgar measures interventions needed to achieve this condition. We hypothesized that the combination of both (Combined-Apgar) describes postnatal condition of preterm infants better than either of the scores alone. Methods: Scores were assessed in preterm infants below 32 completed weeks of gestation. Data were prospectively collected in 20 NICU in 12 countries. Prediction of poor outcome (death, severe/moderate BPD, IVH, CPL and ROP) was used as a surrogate parameter to compare the scores. To compare predictive value the AUC for the ROC was calculated. Results: Of 2150 eligible newborns, data on 1855 infants with a mean GA of 286/7± 23/7 weeks were analyzed. At 1 minute, the Combined-Apgar was significantly better in predicting poor outcome than the Specified- or Expanded-Apgar alone. Of infants with a very low score at 5 or 10 minutes 81% or 100% had a poor outcome, respectively. In these infants the relative risk (RR) for perinatal mortality was 24.93 (13.16-47.20) and 31.34 (15.91-61.71), respectively. Conclusion: The Combined-Apgar allows a more appropriate description of infant’s condition under conditions of modern neonatal care. It should be used as a tool for better comparison of group of infants and postnatal interventions.

Published
2015

15. Genetic variation in T(H)17 pathway genes, childhood asthma, and total serum IgE levels

Author

Schieck, Maximilian, Michel, Sven, Suttner, Kathrin, Illig, Thomas, Zeilinger, Sonja, Franke, Andre, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, Kerzel, Sebastian, Kabesch, Michael, Schieck, Maximilian, Michel, Sven, Suttner, Kathrin, Illig, Thomas, Zeilinger, Sonja, Franke, Andre, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, Kerzel, Sebastian, and Kabesch, Michael

Published
2014

16. Genetic variation in T(H)17 pathway genes, childhood asthma, and total serum IgE levels

Author

Schieck, Maximilian, Michel, Sven, Suttner, Kathrin, Illig, Thomas, Zeilinger, Sonja, Franke, Andre, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, Kerzel, Sebastian, Kabesch, Michael, Schieck, Maximilian, Michel, Sven, Suttner, Kathrin, Illig, Thomas, Zeilinger, Sonja, Franke, Andre, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, Kerzel, Sebastian, and Kabesch, Michael

Published
2014

17. Genetic variants in Protocadherin-1, bronchial hyper-responsiveness, and asthma subphenotypes in German children

Author

Toncheva, Antoaneta A., Suttner, Kathrin, Michel, Sven, Klopp, Norman, Illig, Thomas, Balschun, Tobias, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, von Mutius, Erika, Kabesch, Michael, Toncheva, Antoaneta A., Suttner, Kathrin, Michel, Sven, Klopp, Norman, Illig, Thomas, Balschun, Tobias, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, von Mutius, Erika, and Kabesch, Michael

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.

Published
2012

18. Genetic variants in Protocadherin-1, bronchial hyper-responsiveness, and asthma subphenotypes in German children

Author

Toncheva, Antoaneta A., Suttner, Kathrin, Michel, Sven, Klopp, Norman, Illig, Thomas, Balschun, Tobias, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, von Mutius, Erika, Kabesch, Michael, Toncheva, Antoaneta A., Suttner, Kathrin, Michel, Sven, Klopp, Norman, Illig, Thomas, Balschun, Tobias, Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, von Mutius, Erika, and Kabesch, Michael

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.

Published
2012

19. Unifying Candidate Gene and GWAS Approaches in Asthma

Author

Michel, Sven, Liang, Liming, Depner, Martin, Klopp, Norman, Ruether, Andreas, Kumar, Ashish, Schedel, Michaela, Vogelberg, Christian, von Mutius, Erika, von Berg, Andrea, Bufe, Albrecht, Rietschel, Ernst, Heinzmann, Andrea, Laub, Otto, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, Gut, Ivo G., Schreiber, Stefan, Lathrop, Mark, Illig, Thomas, Kabesch, Michael, Michel, Sven, Liang, Liming, Depner, Martin, Klopp, Norman, Ruether, Andreas, Kumar, Ashish, Schedel, Michaela, Vogelberg, Christian, von Mutius, Erika, von Berg, Andrea, Bufe, Albrecht, Rietschel, Ernst, Heinzmann, Andrea, Laub, Otto, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, Gut, Ivo G., Schreiber, Stefan, Lathrop, Mark, Illig, Thomas, and Kabesch, Michael

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.

Published
2010

20. Unifying Candidate Gene and GWAS Approaches in Asthma

Author

Michel, Sven, Liang, Liming, Depner, Martin, Klopp, Norman, Ruether, Andreas, Kumar, Ashish, Schedel, Michaela, Vogelberg, Christian, von Mutius, Erika, von Berg, Andrea, Bufe, Albrecht, Rietschel, Ernst, Heinzmann, Andrea, Laub, Otto, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, Gut, Ivo G., Schreiber, Stefan, Lathrop, Mark, Illig, Thomas, Kabesch, Michael, Michel, Sven, Liang, Liming, Depner, Martin, Klopp, Norman, Ruether, Andreas, Kumar, Ashish, Schedel, Michaela, Vogelberg, Christian, von Mutius, Erika, von Berg, Andrea, Bufe, Albrecht, Rietschel, Ernst, Heinzmann, Andrea, Laub, Otto, Simma, Burkhard, Frischer, Thomas, Genuneit, Jon, Gut, Ivo G., Schreiber, Stefan, Lathrop, Mark, Illig, Thomas, and Kabesch, Michael

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.

Published
2010

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