A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis.

• Human Molecular Genetics
• Advance Access
• 10.1093/hmg/ddt317
• A genome-wide association study of atopic dermatitis identifies loci 
• with overlapping effects on asthma and psoriasis

1. Stephan Weidinger1,2,†‡, 
2. Saffron A.G. Willis-Owen3,†‡, 
3. Yoichiro Kamatani4,†‡,
4. Hansjörg Baurecht1,2, 
5. Nilesh Morar3,5, 
6. Liming Liang6,7, 
7. Pauline Edser3, 
8. Teresa Street8,
9. Elke Rodriguez1,2, 
10. Grainne M O'regan9,10, 
11. Paula Beattie11, 
12. Regina Fölster-Holst12,
13. Andre Franke2, 
14. Natalija Novak13, 
15. Caoimhe M. Fahy14, 
16. Mårten C.G. Winge15,16,
17. Michael Kabesch20, 
18. Thomas Illig21,22, 
19. Simon Heath23, 
20. Cilla Söderhäll17, 
21. Erik Melén18,24,
22. Göran Pershagen18, 
23. Juha Kere19,25,26, 
24. Maria Bradley15,16, 
25. Agne Lieden16,
26. Magnus Nordenskjold16, 
27. John I. Harper27,28, 
28. W.H. Irwin Mclean29, 
29. Sara J. Brown29,
30. William O.C. Cookson3, 
31. G. Mark Lathrop4,23,30, 
32. Alan D. Irvine9,10,14 and
33. Miriam F. Moffatt3,*

+Author Affiliations

1. ¹Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein and
2. ²Christian-Albrechts-University of Kiel, Kiel, Germany
3. ³National Heart and Lung Institute, Imperial College, London SW3 6LY, UK
4. ⁴Fondation Jean Dausset—Centre d’Étude du Polymorphisme Humain, Paris, France
5. ⁵Department of Dermatology, Chelsea and Westminster Hospital, Fulham Road, London SW10 9NH, UK
6. ⁶Department of Epidemiology and
7. ⁷Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA
8. ⁸Department of Statistics, University of Oxford, Oxford OX1 3TG, UK
9. ⁹National Children's Research Centre and
10. ¹⁰Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin 12, Ireland
11. ¹¹Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ, UK
12. ¹²Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
13. ¹³Department of Dermatology and Allergy, University of Bonn, Bonn, Germany
14. ¹⁴Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland
15. ¹⁵Dermatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
16. ¹⁶Department of Molecular Medicine and Surgery, Center for Molecular Medicine and
17. ¹⁷Department of Biosciences and Nutrition and
18. ¹⁸Institute of Environmental Medicine and
19. ¹⁹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
20. ²⁰Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Campus St. Hedwig, Germany
21. ²¹Institute of Epidemiology, Helmholtz Zentrum Munich, Munich, Germany
22. ²²Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
23. ²³CEA/Centre National de Genotypage, 91057 Evry, France
24. ²⁴Sach's Children's Hospital, Stockholm, Sweden
25. ²⁵Science for Life Laboratory, Stockholm, Sweden
26. ²⁶Research Programs Unit, University of Helsinki and Folkhälsan Institute of Genetics, Helsinki, Finland
27. ²⁷Department of Immunobiology and Dermatology, UCL Institute of Child Health, London, UK
28. ²⁸Department of Paediatric Dermatology, Great Ormond Street Hospital for Children, London, UK
29. ²⁹Dermatology and Genetic Medicine, College of Life Sciences, and College of Medicine, Dentistry and Nursing, University of Dundee, Dundee DD1 5EH, UK
30. ³⁰McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, Canada

1. ↵*To whom correspondence should be addressed at: National Heart and Lung Institute, Imperial College London SW3 6LY, UK. Tel: +44 2075942942; Fax: +44 2073518126; Email:m.moffatt@imperial.ac.uk

• Received December 20, 2012.
• Revision received June 28, 2013.
• Accepted June 28, 2013.

Abstract

Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci.

• © The Author 2013. Published by Oxford University Press.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

This Article

1. Hum. Mol. Genet. (2013)doi: 10.1093/hmg/ddt317First published online: July 25, 2013

1. This article is Open Access

   1. » AbstractFree

   1. Full Text (HTML)Free

   1. Full Text (PDF)Free

   1. Supplementary Data

   

   
   

Vol. 161, No. 4, 2013

Issue release date: July 2013

Citation Download

 Free Supplementary Material

Int Arch Allergy Immunol 2013;161:369-377
(DOI:10.1159/000351404)

Fulltext PDF (240 Kb)

Original Paper

Clinically Relevant Effect of a New Intranasal Therapy (MP29-02) in Allergic Rhinitis Assessed by Responder Analysis Meltzer E.a · Ratner P.c · Bachert C.g · Carr W.b · Berger W.b · Canonica G.W.h ·Hadley J.e · Lieberman P.f · Hampel F.C.d · Mullol J.i · Munzel U.j · Price D.m ·Scadding G.n · Virchow J.C.k · Wahn U.l · Murray R.o · Bousquet J.p  aAllergy and Asthma Medical Group and Research Center, San Diego, Calif.,bAllergy and Asthma Associates of Southern California, Mission Viejo, Calif.,cSylvana Research, San Antonio, Tex.,dCentral Texas Health Research, New Braunfels, Tex.,eUniversity of Rochester Medical Center, Rochester, N.Y.,fUniversity of Tennessee College of Medicine, Memphis, Tenn., USA;gUpper Airways Research Laboratory, Ghent University Hospital, Ghent, Belgium;hUniversity of Genoa, IRCCS AOU S. Martino, Genoa, Italy;iHospital Clínic, IDIBAPS, CIBERES, Barcelona, Spain;jMEDA Pharma GmbH & Co. KG, Bad Homburg,kUniversity Hospital, Rostock, andlChildren's Hospital Charité, Berlin, Germany; mUniversity of Aberdeen, Aberdeen, andnThe Royal National Throat, Nose and Ear Hospital, London, UK;oMedScript, Dundalk, Ireland;pArnaud de Villeneuve University Hospital, Montpellier and Inserm CESP1018, Montpellier, France  Corresponding Author

---

 Outline

• Key Words

• Abstract
• Introduction
• Background and Objectives
• Scientific Background and Explanation of Rationale
• Specific Objectives
• Material and Methods
• Participants
• Planned Interventions and Timing
• Efficacy Variables
• Sample Size, Randomization and Blinding
• Statistical Analyses
• Results
• Patients
• Outcomes
• Original Analysis
• Post hoc Analyses
• Discussion
• Acknowledgements
• References

• Author Contacts
• Article Information
• Publication Details
• Drug Dosage / Copyright

---

  Key Words


• Allergic rhinitis
• Azelastine
• Fluticasone
• MP29-02
• Responder analysis
• Severe chronic upper airway disease 


---

  Abstract

Background: It is unclear what constitutes a clinically meaningful response for allergic rhinitis (AR) outcomes. The objectives of these post hoc analyses were (1) to define a clinically meaningful response using novel efficacy analyses (including a responder analysis), and (2) to compare the efficacy of MP29-02 [a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP)] with commercially available FP, AZE and placebo in seasonal AR (SAR) patients, using these novel analyses.Methods: 610 moderate-to-severe SAR patients (≥12 years old) were randomized into a double-blind, placebo-controlled, 14-day, parallel-group trial. Change from baseline in the reflective total nasal symptom score (rTNSS) over 14 days was the primary outcome. Post hoc endpoints included the sum of nasal and ocular symptoms (rT7SS), efficacy by disease severity and by predominant nasal symptom, and a set of responder analyses.Results: MP29-02 most effectively reduced rT7SS (relative greater improvement: 52% to FP; 56% to AZE) and both nasal and ocular symptoms irrespective of severity. More MP29-02 patients achieved a ≥30, ≥50, ≥60, ≥75 and ≥90% rTNSS reduction, which occurred days faster than with either active comparator; MP29-02 alone was superior to placebo at the ≥60% (or higher) threshold. One in 2 MP29-02 patients achieved a ≥50% rTNSS reduction and 1 in 6 achieved complete/near-to-complete response. Only MP29-02 was consistently superior to placebo for all patients, whatever their predominant symptom. Conclusions: MP29-02 provided faster and more complete symptom control than first-line therapies. It was consistently superior irrespective of severity, response criteria or patient-type, and may be considered the drug of choice for moderate-to-severe AR. These measures define a new standard for assessing relevance in AR.

Copyright © 2013 S. Karger AG, Basel