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

Abstract

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.

Genome-Wide Association Study of Polymorphisms Predisposing to Bronchiolitis

“…Of those variants, rs269094 is a known eQTL for KCND3 , which has been linked to diverse functions including regulation of neurotransmitter release and heart rate 20 . More recently, the gene has also been associated with diisocyanite-induced occupational asthma and cytokine response in smallpox vaccine recipients 23 24 . At the protein level, KCND3 interacts with another membrane protein, DPP10, of which genetic variants have been associated with conditions including asthma 20 25 .…”

Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension

“…Among them, the aforementioned cardiorespiratory phenotypes remained on the list. Seven GWAS SNPs, located upstream from the FIGN gene, were responsible for this enrichment: rs16849225,36 37 rs1189140138 and rs144646839 for systolic blood pressure; rs1300257340 and rs1684921139 for pulse pressure measurement; rs76833157 and rs7576072 for both asthma and response to diisocyanate 41. Furthermore, one variant from a dbGAP study was associated with tunica media wall thickness of carotid arteries (rs1370493, pha003034-phs000221) 42.…”

Ensemble genomic analysis in human lung tissue identifies novel genes for chronic obstructive pulmonary disease

“…Community 113 includes the Sherlock-derived gene CDH23 (cadherin-related 23), involved in cell-cell adhesion and perhaps EMT as a calcium-dependent cell adhesion molecule [ 34 ]. This gene was contained within sub-threshold loci in GWAS of lung function decline [ 35 ], occupational asthma [ 36 ], and age at smoking initiation [ 37 ]. DSP (desmoplakin) was in a community (ID = 179) validated by differential expression but not differential methylation.…”