Genome-Wide Association Study Identifies HLA-DP as a Susceptibility Gene for Pediatric Asthma in Asian Populations

Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P<1×10−8) in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls) and in Korean samples (835 cases and 421 controls). SNP rs987870, located between HLA-DPA1 and HLA-DPB1, was consistently associated with pediatric asthma in 3 independent populations (P combined = 2.3×10−10, odds ratio [OR] = 1.40). HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5×10−10, OR = 1.52, and DPB1*0901: P = 2.0×10−7, OR = 1.49). Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations.

[1]  V. Backer,et al.  Relationship between type 1 diabetes and atopic diseases in a twin population , 2011, Allergy.

[2]  Cedric E. Ginestet.  ggplot2: Elegant Graphics for Data Analysis , 2011 .

[3]  Y. Kokubo,et al.  A genome-wide association study of hypertension-related phenotypes in a Japanese population. , 2010, Circulation journal : official journal of the Japanese Circulation Society.

[4]  Florence Demenais,et al.  A large-scale, consortium-based genomewide association study of asthma. , 2010, The New England journal of medicine.

[5]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[6]  J. Carlson,et al.  HLA DPA1, DPB1 Alleles and Haplotypes Contribute to the Risk Associated With Type 1 Diabetes , 2010, Diabetes.

[7]  T. Arinami,et al.  S2554X mutation in the filaggrin gene is associated with allergen sensitization in the Japanese population. , 2010, The Journal of allergy and clinical immunology.

[8]  E. Bleecker,et al.  Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions. , 2010, The Journal of allergy and clinical immunology.

[9]  Ingo Ruczinski,et al.  Variants of DENND1B associated with asthma in children. , 2010, The New England journal of medicine.

[10]  J. Bousquet,et al.  Allergic rhinitis and its impact on asthma update (ARIA 2008)--western and Asian-Pacific perspective. , 2009, Asian Pacific journal of allergy and immunology.

[11]  M. Xiong,et al.  HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans. , 2009, Arthritis and rheumatism.

[12]  R. Vierkant,et al.  Replication of rubella vaccine population genetic studies: validation of HLA genotype and humoral response associations. , 2009, Vaccine.

[13]  Hadley Wickham,et al.  ggplot2 - Elegant Graphics for Data Analysis (2nd Edition) , 2017 .

[14]  P. Sullivan,et al.  Genome-Wide Association Study Implicates Chromosome 9q21.31 as a Susceptibility Locus for Asthma in Mexican Children , 2009, PLoS genetics.

[15]  Ingo Ruczinski,et al.  Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. , 2009, American journal of human genetics.

[16]  Choon-Sik Park,et al.  The HLA DRB1*1501-DQB1*0602-DPB1*0501 Haplotype Is a Risk Factor for Toluene Diisocyanate-Induced Occupational Asthma , 2009, International Archives of Allergy and Immunology.

[17]  G. Abecasis,et al.  Genotype imputation. , 2009, Annual review of genomics and human genetics.

[18]  Wei Chen,et al.  GWAS GUI: graphical browser for the results of whole-genome association studies with high-dimensional phenotypes , 2009, Bioinform..

[19]  T. Nakahata,et al.  Changing prevalence and severity of childhood allergic diseases in kyoto, Japan, from 1996 to 2006. , 2009, Allergology international : official journal of the Japanese Society of Allergology.

[20]  S. Fujieda,et al.  Association of serum interleukin‐33 level and the interleukin‐33 genetic variant with Japanese cedar pollinosis , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[21]  Yusuke Nakamura,et al.  Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. , 2008, American journal of human genetics.

[22]  M. Sohn,et al.  Combined effect of tumour necrosis factor‐α and interleukin‐13 polymorphisms on bronchial hyperresponsiveness in Korean children with asthma , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[23]  Anbupalam Thalamuthu,et al.  TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study. , 2007, The New England journal of medicine.

[24]  Gonçalo R. Abecasis,et al.  Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma , 2007, Nature.

[25]  Yusuke Nakamura,et al.  Functional polymorphism in the suppressor of cytokine signaling 1 gene associated with adult asthma. , 2007, American journal of respiratory cell and molecular biology.

[26]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[27]  L. Fu,et al.  Prevalence of atopy in children with type 1 diabetes mellitus in central Taiwan. , 2007, Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi.

[28]  R. Vierkant,et al.  Human leukocyte antigen and interleukin 2, 10 and 12p40 cytokine responses to measles: is there evidence of the HLA effect? , 2006, Cytokine.

[29]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[30]  K. Lue,et al.  Distribution of allergens in children with different atopic disorders in central Taiwan. , 2006, Acta paediatrica Taiwanica = Taiwan er ke yi xue hui za zhi.

[31]  Yusuke Nakamura,et al.  Functional haplotypes of IL-12B are associated with childhood atopic asthma. , 2005, The Journal of allergy and clinical immunology.

[32]  Choon-Sik Park,et al.  HLA association in aspirin-intolerant asthma: DPB1*0301 as a strong marker in a Korean population. , 2004, The Journal of allergy and clinical immunology.

[33]  Maria Pia Sormani,et al.  A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismatches for hematologic stem cell transplantation. , 2003, Blood.

[34]  Pak Chung Sham,et al.  Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits , 2003, Bioinform..

[35]  J. Warner,et al.  HLA class II genotype, HLA-DR B cell surface expression and allergen specific IgE production in atopic and non-atopic members of asthmatic family pedigrees. , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[36]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[37]  T. Sasazuki,et al.  HLA class II alleles in Japanese patients with inflammatory bowel disease. , 1999, Tissue antigens.

[38]  Johansson,et al.  Increasing prevalence of asthma over 12 years among dairy farmers on Gotland, Sweden: storage mites remain dominant allergens , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[39]  E. Noguchi,et al.  Distribution of IgE and IgG antibody levels against house dust mites in schoolchildren, and their relation with asthma. , 1997, The Journal of asthma : official journal of the Association for the Care of Asthma.

[40]  A. Kimura,et al.  Comprehensive analysis of HLA genes in Takayasu arteritis in Japan. , 1996, International journal of cardiology.

[41]  C. Glass,et al.  RXRβ: A coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements , 1991, Cell.

[42]  G. Ferrara,et al.  Frequency of DPB1*0401 is significantly decreased in patients with allergic asthma in a mulatto population. , 1991, Human immunology.

[43]  S. Isoyama,et al.  Relationship between asthma and seasonal allergic rhinitis in schoolchildren. , 1990, Annals of allergy.