Genome-wide association study of recalcitrant atopic dermatitis in Korean children.
BACKGROUND
Atopic dermatitis (AD) is a heterogeneous chronic inflammatory skin disease. Most AD during infancy resolves during childhood, but moderate-to-severe AD with allergic sensitization is more likely to persist into adulthood and more often occurs with other allergic diseases.


OBJECTIVE
We sought to find susceptibility loci by performing the first genome-wide association study (GWAS) of AD in Korean children with recalcitrant AD, which was defined as moderate-to-severe AD with allergic sensitization.


METHODS
Our study included 246 children with recalcitrant AD and 551 adult control subjects with a negative history of both allergic disease and allergic sensitization. DNA from these subjects was genotyped; sets of common single nucleotide polymorphisms (SNPs) were imputed and used in the GWAS after quality control checks.


RESULTS
SNPs at a region on 13q21.31 were associated with recalcitrant AD at a genome-wide threshold of significance (P < 2.0 × 10(-8)). These associated SNPs are more than 1 Mb from the closest gene, protocadherin (PCDH)9. SNPs at 4 additional loci had P values of less than 1 × 10(-6), including SNPs at or near the neuroblastoma amplified sequence (NBAS; 2p24.3), thymus-expressed molecule involved in selection (THEMIS; 6q22.33), GATA3 (10p14), and S-phase cyclin A-associated protein in the ER (SCAPER; 15q24.3) genes. Further analysis of total serum IgE levels suggested 13q21.31 might be primarily an IgE locus, and analyses of published data demonstrated that SNPs at the 15q24.3 region are expression quantitative trait loci for 2 nearby genes, ISL2 and proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), in immune cells.


CONCLUSIONS
Our GWAS of recalcitrant AD identified new susceptibility regions containing genes involved in epithelial cell function and immune dysregulation, 2 key features of AD, and potentially extend our understanding of their role in pathogenesis.
Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Human Genetics, University of Chicago, Chicago, Ill.
Kyung Won
KW
Kim
Department of Human Genetics, University of Chicago, Chicago, Ill.
Rachel A
RA
Myers
Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea.
Ji Hyun
JH
Lee
Department of Human Genetics, University of Chicago, Chicago, Ill.
Catherine
C
Igartua
Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Kyung Eun
KE
Lee
Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Yoon Hee
YH
Kim
Division of Allergy and Chronic Respiratory Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Korea.
Eun-Jin
EJ
Kim
Division of Allergy and Chronic Respiratory Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Korea.
Dankyu
D
Yoon
Division of Allergy and Chronic Respiratory Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Korea.
Joo-Shil
JS
Lee
Laboratory for Respiratory and Allergic Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
Tomomitsu
T
Hirota
Laboratory for Respiratory and Allergic Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
Mayumi
M
Tamari
Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
Atsushi
A
Takahashi
Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
Michiaki
M
Kubo
Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
Je-Min
JM
Choi
Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Kyu-Earn
KE
Kim
Department of Human Genetics, University of Chicago, Chicago, Ill; Department of Medicine and Statistics, University of Chicago, Chicago, Ill.
Dan L
DL
Nicolae
Department of Human Genetics, University of Chicago, Chicago, Ill.
Carole
C
Ober
Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. Electronic address: mhsohn@yuhs.ac.
Myung Hyun
MH
Sohn
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000293:Adolescent; D000328:Adult; D044466:Asian People; D015820:Cadherins / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002882:Chromosomes, Human, Pair 13; D002884:Chromosomes, Human, Pair 15; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology; D003876:Dermatitis, Atopic / Q000208:ethnology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics* / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D000091363:Protocadherins; D040641:Quantitative Trait Loci; D012720:Severity of Illness Index; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C516210:ISL2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060850:LIM-Homeodomain Proteins; C117339:NBAS protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C115817:PCDH9 protein, human; C486382:PSTPIP1 protein, human; D000091363:Protocadherins; C523211:SCAPER protein, human; D014157:Transcription Factors; C557796:thymocyte-expressed molecule involved in selection, human; D007073:Immunoglobulin E
Genome-wide association study; IgE; allergic sensitization; atopic dermatitis; children; severity