CTNNA3 ( -Catenin) Gene Variants Are Associated With Diisocyanate Asthma: A Replication Study in a Caucasian Worker Population

Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Toxicological Sciences (Impact Factor: 3.85). 09/2012; 131(1). DOI: 10.1093/toxsci/kfs272
Source: PubMed


Recently, a genome wide association study (GWAS) conducted in Korean subjects identified three CTNNA3 (alpha-T catenin) single nucleotide polymorphisms (SNPs) (rs10762058, rs7088181, and rs4378283) associated with diisocyanate induced occupational asthma (DA). The CTNNA3 gene codes for a cadherin involved in formation of stretch-resistant cell-cell adhesions. We conducted a candidate gene association study to replicate these findings in Caucasian workers. Genotyping was performed on DNA using a 5' nuclease PCR assay collected from 410 diisocyanate exposed and predominantly Canadian workers including: 132 workers with DA confirmed by a specific inhalation challenge (DA+); 131 symptomatic workers in whom DA was excluded by a negative challenge (DA-); and 147 HDI-exposed asymptomatic workers (AWs). As in the Korean study, highly linked CTNNA3 rs7088181 and rs10762058 SNPs were significantly associated with DA+ when compared to AWs but not in comparison to DA- workers (p≤ 0.05). After adjusting for potentially confounding variables of age, smoking status and duration of exposure, minor allele homozygotes of rs7088181 and rs10762058 SNPs were at increased risk for DA compared with AWs [OR= 9.05 (95% CI:1.69, 48.54) and OR = 6.82 (95% CI:1.65, 28.24), respectively]. In conclusion, we replicated results from the only reported GWAS study of DA demonstrating an association between two closely linked CTNNA3 gene SNPs and DA. These findings lend further support to the clinical relevance of these genotypes in predicting susceptibility to DA and the potential importance of cadherins in the disease process.

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    • "susceptibility locus in the Korean study and replicated by our group (Bernstein et al., 2013). The overlapping regions have been presented in Supplementary Table 4 "
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    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 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 two of the suggestive SNPs (rs2446823 and rs2446824) are located within putative binding sites for the CEBPA/B and HNF4A transcription factors (TF), respectively. The present 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 two suggestive SNPs with likely transcription factor 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. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email:
    Toxicological Sciences 04/2015; 146(1). DOI:10.1093/toxsci/kfv084 · 3.85 Impact Factor
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    • "In an attempt to further define risk for DA, numerous investigators have conducted candidate gene association studies among workers with DA including those assessing immune response genes (i.e., HLA class II alleles), candidate single nucleotide polymorphism (SNP) variants of antioxidant enzyme genes (e.g., glutathione transferase polymorphisms), and Th2 cytokine genes (Balboni et al., 1996; Bernstein, 2011; Mapp et al., 2002). Although significant SNP associations have been identified, in association with DA, most have not been replicated in other DI worker populations (Choi et al., 2009; Rihs et al., 1997) with the exception of two polymorphisms of the CTNNA3 (α-catenin) gene reported to be significantly associated with DA in both Caucasian and South Korean DI-exposed workers (Bernstein et al., 2012; Kim et al., 2009). "
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    ABSTRACT: Risk factors have not been identified that determine susceptibility for development of diisocyanate induced occupational asthma (DA). We hypothesized that diisocyanate exposure could modify gene promoter regions regulating transcription of cytokine mediators and thereby influence expression of DA. A cross-sectional study was designed to investigate the promoter methylation status of candidate genes in diisocyanate exposed workers. Subjects consisted of 131 workers in three groups: 40 cases with DA confirmed by a positive specific inhalation challenge (SIC) (DA+); 41 exposed workers with lower respiratory symptoms and negative SIC (DA-); and 50 asymptomatic exposed workers (AW). We studied four candidate genes (GSTM1, DUSP22, IFN-γ, and IL-4) for which altered promoter methylation has been previously investigated for relationships with a variety of other environmental exposures. Methylation status was determined using methylation-specific-quantitative PCR performed on genomic DNA extracted from whole blood. Results showed that relative methylation of IFN-γ promoter was significantly increased in DA+ in comparison to both comparator groups (DA- and AW); and it exhibited good sensitivity (77.5%) and specificity (80%) for identifying DA workers in a multivariate predictive model after adjusting for type of DI exposure, smoking status, methacholine PC20 and gender. IL-4 promoter was slightly less methylated only in DA+ compared to AW among non-smoking workers. Both GSTM1 and DUSP22 promoter methylations were found not associated with DA. Our finding suggests that exposure to occupational chemicals could play a heretofore undefined mechanistic role via epigenetic modification of specific genes in the promoter region.
    Toxicological Sciences 03/2013; 133(2). DOI:10.1093/toxsci/kft079 · 3.85 Impact Factor
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    ABSTRACT: This review aims to update the knowledge on the burden of disease due to exposure to isocyanates. Health effects of isocyanates and their major products, polyurethanes, are mainly determined by sensitization to isocyanates. Recent studies on the genetic factors to explain individual susceptibility to sensitization are reviewed. Production of isocyanates has rapidly increased in the past and is predicted to increase at an annual rate of around 5%. Consumer products and the construction area are the main drivers of growth. This leads to increased nonoccupational exposure. The use of sprayed polyurethane foams for insulation in existing homes is one such example of nonoccupational exposure. The percentage of people exposed who show health effects is not known. Occupational exposure increases are mainly caused by the increase in the workforce. The percentage of workers exhibiting health effects remained fairly stable at 5-15% in the last decade. To explain why not all people exposed to isocyanates develop adverse health effects, recent findings on sensitization to isocyanate are reviewed. The skin is the most important route for sensitization. Increased production of isocyanates and rising use of these substances in consumer products is leading to an increased burden of disease, with an increase in nonoccupational exposure as well. Sensitization to isocyanates is the main route for adverse health effects. The skin is the major route for sensitization. Recently, several genetic factors have been identified that play a role in the individual susceptibility for sensitization.
    Current opinion in pulmonary medicine 12/2013; 20(2). DOI:10.1097/MCP.0000000000000029 · 2.76 Impact Factor
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