Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.
Diisocyanates, reactive chemicals used to produce polyurethane products, are the most common causes of occupational asthma. The aim of this study is to identify susceptibility gene variants that could contribute to the pathogenesis of diisocyanate asthma (DA) using a Genome-Wide Association Study (GWAS) approach. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed in 74 diisocyanate-exposed workers with DA and 824 healthy controls using Omni-2.5 and Omni-5 SNP microarrays. We identified 11 SNPs that exceeded genome-wide significance; the strongest association was for the rs12913832 SNP located on chromosome 15, which has been mapped to the HERC2 gene (p = 6.94 × 10(-14)). Strong associations were also found for SNPs near the ODZ3 and CDH17 genes on chromosomes 4 and 8 (rs908084, p = 8.59 × 10(-9) and rs2514805, p = 1.22 × 10(-8), respectively). We also prioritized 38 SNPs with suggestive genome-wide significance (p < 1 × 10(-6)). Among them, 17 SNPs map to the PITPNC1, ACMSD, ZBTB16, ODZ3, and CDH17 gene loci. Functional genomics data indicate that 2 of the suggestive SNPs (rs2446823 and rs2446824) are located within putative binding sites for the CCAAT/Enhancer Binding Protein (CEBP) and Hepatocyte Nuclear Factor 4, Alpha transcription factors (TFs), respectively. This study identified SNPs mapping to the HERC2, CDH17, and ODZ3 genes as potential susceptibility loci for DA. Pathway analysis indicated that these genes are associated with antigen processing and presentation, and other immune pathways. Overlap of 2 suggestive SNPs with likely TF binding sites suggests possible roles in disruption of gene regulation. These results provide new insights into the genetic architecture of DA and serve as a basis for future functional and mechanistic studies.
*Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Berran
B
Yucesoy
Cincinnati Children's Hospital Medical Center, Center for Autoimmune Genomics and Etiology, and Cincinnati VA Medical Center.
Kenneth M
KM
Kaufman
*Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio,Cincinnati Children's Hospital Medical Center, Center for Autoimmune Genomics and Etiology, and Cincinnati VA Medical Center,Cincinnati Children's Hospital Medical Center, Divisions of Biomedical Informatics and Developmental Biology,Cincinnati Children's Hospital Medical Center, Division of Human Genetics,Université de Montréal, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada,Université Laval, Hôpital Laval, Sainte-Foy, Québec, Canada,Department of Allergy, Fundación Jiménez Díaz and CIBER de Enfermedades Respiratorias CIBERES, Madrid, Spain,Department of Allergy, Hospital La Paz-IdiPAZ and CIBER de Enfermedades Respiratorias CIBERES, Madrid, Spain,University of Toronto, Toronto, Ontario, Canada and**Hospitals Vall D'Hebron, Barcelona and CIBER de Enfermedades Respiratorias CIBERES, Madrid, Spain.
Zana L
ZL
Lummus
Cincinnati Children's Hospital Medical Center, Center for Autoimmune Genomics and Etiology, and Cincinnati VA Medical Center, Cincinnati Children's Hospital Medical Center, Divisions of Biomedical Informatics and Developmental Biology.
Matthew T
MT
Weirauch
Cincinnati Children's Hospital Medical Center, Division of Human Genetics.
Ge
G
Zhang
Université de Montréal, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada.
André
A
Cartier
Université Laval, Hôpital Laval, Sainte-Foy, Québec, Canada.
Louis-Philippe
LP
Boulet
Department of Allergy, Fundación Jiménez Díaz and CIBER de Enfermedades Respiratorias CIBERES, Madrid, Spain.
Joaquin
J
Sastre
Department of Allergy, Hospital La Paz-IdiPAZ and CIBER de Enfermedades Respiratorias CIBERES, Madrid, Spain.
Santiago
S
Quirce
University of Toronto, Toronto, Ontario, Canada and.
Susan M
SM
Tarlo
**Hospitals Vall D'Hebron, Barcelona and CIBER de Enfermedades Respiratorias CIBERES, Madrid, Spain.
Maria-Jesus
MJ
Cruz
**Hospitals Vall D'Hebron, Barcelona and CIBER de Enfermedades Respiratorias CIBERES, Madrid, Spain.
Xavier
X
Munoz
Cincinnati Children's Hospital Medical Center, Center for Autoimmune Genomics and Etiology, and Cincinnati VA Medical Center.
John B
JB
Harley
*Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio, bernstdd@ucmail.uc.edu.
David I
DI
Bernstein
D001249:Asthma / Q000139:chemically induced / Q000235:genetics*; D003485:Cyanates / Q000633:toxicity*; D055106:Genome-Wide Association Study; D006801:Humans; D009784:Occupational Diseases / Q000235:genetics*
D003485:Cyanates
asthma; diisocyanate; genetic polymorphism; genome-wide association study