Online citations, reference lists, and bibliographies.
Please confirm you are human
(Sign Up for free to never see this)
← Back to Search

Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.

B. Yucesoy, K. Kaufman, Z. Lummus, Matthew T. Weirauch, Ge Zhang, A. Cartier, L. Boulet, J. Sastre, S. Quirce, S. Tarlo, M. Cruz, X. Muñoz, J. Harley, D. Bernstein
Published 2015 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
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.
This paper references
10.1164/AJRCCM.159.6.9806159
Occupational asthma caused by isocyanates: patterns of asthmatic reactions to increasing day-to-day doses.
J. Malo (1999)
10.1016/S1081-1206(10)60972-6
Diisocyanate asthma and gene-environment interactions with IL4RA, CD-14, and IL-13 genes.
D. Bernstein (2006)
10.1016/j.jaci.2011.03.007
Hexamethylene diisocyanate asthma is associated with genetic polymorphisms of CD14, IL-13, and IL-4 receptor α.
David I. Bernstein (2011)
10.1038/nbt1010-1045
The NIH Roadmap Epigenomics Mapping Consortium
B. Bernstein (2010)
10.1093/nar/gks1114
BioGPS and MyGene.info: organizing online, gene-centric information
C. Wu (2013)
10.1073/pnas.0902426106
NPAS3 is a trachealess homolog critical for lung development and homeostasis
S. Zhou (2009)
10.1081/JAS-120000801
Occupational Asthma
A. Draper (2002)
10.1038/ncb2008
HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes
S. Bekker-Jensen (2010)
10.1016/j.cell.2014.08.009
Determination and Inference of Eukaryotic Transcription Factor Sequence Specificity
Matthew T. Weirauch (2014)
10.1016/j.ajhg.2009.06.011
PRKCA: a positional candidate gene for body mass index and asthma.
A. Murphy (2009)
10.1046/j.1365-2222.2002.01290.x
Isocyanate‐induced occupational asthma in far‐east Asia: pathogenesis to prognosis
H. Park (2002)
10.1016/S0140-6736(11)60874-X
Identification of IL6R and chromosome 11q13.5 as risk loci for asthma
M. A. Ferreira (2011)
10.1093/nar/gkr1055
The UCSC Genome Browser database: extensions and updates 2011
Timothy R. Dreszer (2012)
10.1371/journal.pone.0023714
Identification of KIF3A as a Novel Candidate Gene for Childhood Asthma Using RNA Expression and Population Allelic Frequencies Differences
Melinda Butsch Kovacic (2011)
10.1111/j.1476-5381.1996.tb16087.x
The involvement of sensory neuropeptides in toluene diisocyanate‐induced tracheal hyperreactivity in the mouse airways
H. Scheerens (1996)
10.1097/JOM.0000000000000138
Genetic Variants in the Major Histocompatibility Complex Class I and Class II Genes Are Associated With Diisocyanate-Induced Asthma
B. Yucesoy (2014)
10.1093/nar/gkq537
The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function
David Warde-Farley (2010)
10.1016/S1567-5769(01)00174-6
Diisocyanate asthma: clinical aspects and immunopathogenesis.
C. Redlich (2002)
10.1371/journal.pone.0092993
Assessment of the Biological Pathways Targeted by Isocyanate Using N-Succinimidyl N-Methylcarbamate in Budding Yeast Saccharomyces cerevisiae
G. Azad (2014)
10.1152/AJPLUNG.00475.2005
Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-kappaB via a G(q)-dependent pathway.
R. Williams (2007)
10.1080/15459620902724060
Measurements of Airborne Methylene Diphenyl Diisocyanate (MDI) Concentration in the U.S. Workplace
K. Booth (2009)
10.1111/j.1365-2222.2008.02982.x
Human innate immune responses to hexamethylene diisocyanate (HDI) and HDI–albumin conjugates
A. Wisnewski (2008)
10.1111/j.1469-1809.2010.00584.x
Association of SLC6A12 variants with aspirin‐intolerant asthma in a Korean population
C. F. Pasaje (2010)
10.1093/nar/gkt439
WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013
Jing Wang (2013)
10.1111/j.1365-2222.2008.03117.x
Alpha‐T‐catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate‐induced asthma by genome‐wide association analysis
S. Kim (2009)
10.2174/1874306401206010001
Asthma and COPD - The C/EBP Connection
N. Miglino (2012)
10.1164/AJRCCM.158.1.9704061
Immunization and challenge with toluene diisocyanate decrease tachykinin and calcitonin gene-related peptide immunoreactivity in guinea pig central airways.
C. Mapp (1998)
10.1158/0008-5472.CAN-11-0385
HERC2 Interacts with Claspin and regulates DNA origin firing and replication fork progression.
N. Izawa (2011)
10.1002/1529-0131(200010)43:10<2335::AID-ANR22>3.0.CO;2-W
Juvenile rheumatoid arthritis: linkage to HLA demonstrated by allele sharing in affected sibpairs.
S. Prahalad (2000)
10.1016/J.ANAI.2010.05.002
Work-related sensitization and respiratory symptoms in carpentry apprentices exposed to wood dust and diisocyanates.
P. Campo (2010)
10.1016/J.JACI.2006.07.056
Disease-specific expression and regulation of CCAAT/enhancer-binding proteins in asthma and chronic obstructive pulmonary disease.
P. Borger (2007)
10.1038/ng.148
Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis
A. Franke (2008)
10.1101/gr.128652.111
HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter.
M. Visser (2012)
10.1593/NEO.06376
E3 ubiquitin ligases as cancer targets and biomarkers.
Y. Sun (2006)
10.1097/ACI.0b013e3283449fc9
Genetics of occupational asthma
D. Bernstein (2011)
10.1126/science.1222794
Systematic Localization of Common Disease-Associated Variation in Regulatory DNA
M. Maurano (2012)
10.1093/occmed/kqn007
Fifteen-year trends in occupational asthma: data from the Shield surveillance scheme.
N. Bakerly (2008)
10.1093/toxsci/kfs272
CTNNA3 (α-catenin) gene variants are associated with diisocyanate asthma: a replication study in a Caucasian worker population.
D. Bernstein (2013)
10.1016/0076-6879(90)83015-2
Consensus patterns in DNA.
G. Stormo (1990)
10.1183/09031936.03.00045103
Pathogenesis of occupational asthma
J. Sastre (2003)
10.1093/toxsci/kfs183
Genetic variants in antioxidant genes are associated with diisocyanate-induced asthma.
B. Yucesoy (2012)
10.1186/1479-7364-7-16
Rank-based genome-wide analysis reveals the association of Ryanodine receptor-2 gene variants with childhood asthma among human populations
L. Ding (2013)
10.1126/science.1186176
Five-Vertebrate ChIP-seq Reveals the Evolutionary Dynamics of Transcription Factor Binding
D. Schmidt (2010)
10.1073/pnas.0903103106
Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
L. Hindorff (2009)
10.1038/NATURE11247
An integrated encyclopedia of DNA elements in the human genome
Data production leads (2012)



This paper is referenced by
10.4168/aair.2019.11.2.188
Update on the Management of Occupational Asthma and Work-Exacerbated Asthma
Ambrose Lau (2019)
10.1016/j.fsigen.2018.10.010
Off-target phenotypes in forensic DNA phenotyping and biogeographic ancestry inference: A resource.
C. Bradbury (2019)
Validating Genetic Associations of Asthma in The Consortium of Asthma among African-ancestry Populations in the Americas
Hrafnhildur Bjarnadóttir (2017)
10.33549/PHYSIOLRES.933730
ZBTB16 and metabolic syndrome: a network perspective.
O. Šeda (2017)
10.1097/MCP.0000000000000364
The role of gene–environment interplay in occupational and environmental diseases: current concepts and knowledge gaps
Elizabeth Kwo (2017)
10.1016/j.annepidem.2017.03.002
Opportunities and obstacles in translating evidence to policy in occupational asthma.
S. Tarlo (2018)
10.1101/624908
Legacy Data Confounds Genomics Studies
Luke Anderson-Trocmé (2019)
10.1016/j.jaci.2018.06.022
Genetic variants with gene regulatory effects are associated with diisocyanate‐induced asthma
D. Bernstein (2018)
10.1093/molbev/msz201
Legacy Data Confounds Genomics Studies.
Luke Anderson-Trocmé (2019)
10.1097/JBR.0000000000000026
Integrative omics analysis identifies macrophage migration inhibitory factor signaling pathways underlying human hepatic fibrogenesis and fibrosis
Zhipeng Liu (2019)
10.1016/j.taap.2018.06.019
Toluene diisocyanate exposure and autotaxin–lysophosphatidic acid signalling
Julia M Broström (2018)
10.1016/B978-0-12-800685-6.00013-8
Chapter 13 – Asthma
M. McGeachie (2017)
10.3389/fphys.2019.01014
HERCing: Structural and Functional Relevance of the Large HERC Ubiquitin Ligases
J. García-Cano (2019)
10.1371/journal.pone.0193499
Genomic and transcriptomic comparison of allergen and silver nanoparticle-induced mast cell degranulation reveals novel non-immunoglobulin E mediated mechanisms
Monica M Johnson (2018)
Genetic susceptibility to childhood bronchiolitis
Anu Pasanen (2018)
10.1038/srep41653
Genome-Wide Association Study of Polymorphisms Predisposing to Bronchiolitis
A. Pasanen (2017)
10.3389/fpubh.2020.535116
Building a Population Representative Pediatric Biobank: Lessons Learned From the Greater Cincinnati Childhood Cohort
Lisa J. Martin (2020)
10.3389/fgene.2020.00836
Influence of Genetic Variance on Biomarker Levels After Occupational Exposure to 1,6-Hexamethylene Diisocyanate Monomer and 1,6-Hexamethylene Diisocyanate Isocyanurate
Laura Taylor (2020)
10.1016/J.JAB.2017.03.002
Hits and defeats of genome-wide association studies of atopy and asthma
H. Danielewicz (2017)
10.1101/112953
Genome-wide association study of asthma in individuals of African ancestry reveals novel asthma susceptibility loci
Michelle Daya (2017)
10.33915/etd.5889
Identification of SNPs Potentially Associated with Asthma Using a Di-isocyanate Luciferase Reporter Assay
Wentao Jiang (2019)
10.1136/jmedgenet-2018-105669
Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension
Pau Puigdevall (2019)
Early in Life EpiGenetic Events and the susceptibility to Chronic Inflammatory Lung Diseases
(2018)
10.1186/s40246-018-0132-z
Ensemble genomic analysis in human lung tissue identifies novel genes for chronic obstructive pulmonary disease
J. Morrow (2018)
10.1093/hmg/ddz175
Genome-wide association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema
Å. Johansson (2019)
10.1007/s11882-016-0644-3
Biomarkers in Occupational Asthma
J. Domínguez-Ortega (2016)
10.1080/02770903.2019.1590589
Linking endotypes to omics profiles in difficult-to-control asthma using the diagnostic Chinese medicine syndrome differentiation algorithm
Wenping Song (2019)
10.1186/s12920-020-00768-z
Integrative genomics analysis of various omics data and networks identify risk genes and variants vulnerable to childhood-onset asthma
Xiuqing Ma (2020)
10.1016/B978-0-12-801238-3.64177-6
Systems Biology in Immunotoxicology
B. Yucesoy (2018)
10.15620/CDC58080
Toxicological profile for toluene diisocyanate and methylenediphenyl diisocyanate
Malcolm Williams (2018)
10.3390/ijms21218196
Pathogenic Single Nucleotide Polymorphisms on Autophagy-Related Genes
Isaac Tamargo-Gómez (2020)
10.1101/195933
Genome-wide association analysis of 350,000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema
Å. Johansson (2018)
See more
Semantic Scholar Logo Some data provided by SemanticScholar