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Alpha‐T‐catenin ( CTNNA3 ) gene was identified as a risk variant for toluene diisocyanate‐induced asthma by genome‐wide association analysis

2008; Wiley; Volume: 39; Issue: 2 Linguagem: Inglês

10.1111/j.1365-2222.2008.03117.x

1365-2222

Seung‐Hyun Kim, B. Y. Cho, C. S. Park, Eun‐Soon Shin, E.‐Y. Cho, E‐M. Yang, C.-W. Kim, C‐S. Hong, J‐E. Lee, Hae‐Sim Park,

Occupational exposure and asthma

Summary Background Toluene diisocyanate (TDI) is the most important cause of occupational asthma, but the genetic mechanism of TDI‐induced asthma is still unknown. Objective The objective of the study was to identify susceptibility alleles associated with the TDI‐induced asthma phenotype. Methods We conducted a genome‐wide association study in 84 patients with TDI‐induced asthma and 263 unexposed healthy normal controls using Affymetrix 500K SNPchip. We also investigated the relationships between genetic polymorphisms and transcript levels in Epstein–Barr virus‐transformed lymphoblastoid cell lines from patients with TDI‐induced asthma enrolled in this study. Results Genetic polymorphisms of CTNNA3 (catenin alpha 3, alpha‐T catenin) were significantly associated with the TDI‐induced asthma phenotype (5.84 × 10 −6 for rs10762058, 1.41 × 10 −5 for rs7088181, 2.03 × 10 −5 for rs4378283). Carriers with the minor haplotype, HT2 [GG], of two genetic polymorphisms (rs10762058 and rs7088181) showed significantly lower PC 20 methacholine level ( P =0.041) and lower mRNA expression of CTNNA3 than non‐carriers ( P =0.040). A genetic polymorphism in the 3′ downstream region of CTNNA3 (rs1786929), as identified by DNA direct sequencing, was significantly associated with the TDI‐induced asthma phenotype ( P =0.015 in recessive analysis model) and the prevalence of serum‐specific IgG to cytokeratin 19 ( P =0.031). Conclusion These findings suggested that multiple genetic polymorphisms of CTNNA3 may be determinants of susceptibility to TDI‐induced asthma.