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

Abstract

Recently, a genome-wide association study (GWAS) conducted in Korean subjects identified four CTNNA3 (alpha-T catenin) single nucleotide polymorphisms (SNPs) (rs10762058, rs7088181, rs1786929, 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 hexamethylene diisocyanate-exposed asymptomatic workers (AWs). As in the Korean study, highly linked CTNNA3 rs7088181 and rs10762058 SNPs (but not rs4378283 and rs1786929) were significantly associated with DA+ when compared with AWs but not in comparison with 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 catenins in the disease process.

The cardiac protein αT-catenin contributes to chemical-induced asthma

“…Future studies are required to determine whether ␣T-cat KO mice are more susceptible to models of atopic asthma, which also may be better suited to discerning a molecular mechanism owing to their relative robustness compared with TDI asthma models. Overall, our study has validated the genetic associations of ␣T-cat with TDI asthma and lung mechanics (2,11,21,22), suggesting the potential importance of cardiac cell junction function in the development of occupational asthma.…”

Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy

“…Moreover, CTNNA3 SNPs were identified by a GWAS in Korean subjects with diisocyanate-induced occupational asthma (36). Two of the CTNNA3 SNPs identified in the Korean study were subsequently confirmed in a study of Canadian workers with occupational asthma (37). A recent GWAS demonstrated the association between SNP in CTNNA3 and response to glucocorticoid therapy in childhood asthma (38).…”

Opportunities and obstacles in translating evidence to policy in occupational asthma

“…The mechanism of OA from diisocyanates remains incompletely understood but sensitization does appear to be mediated by immunologic mechanisms, and there are genetic markers that have been associated with OA from diisocyanates [50–53]. Specific IgE antibodies to diisocyanates linked to human albumin have been identified in up to 55% of patients with OA related to diisocyanates [54,55] and have been reported to be very specific for the diagnosis, although having relatively low sensitivity [56].…”