Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis.
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 x 10(-6) for rs10762058, 1.41 x 10(-5) for rs7088181, 2.03 x 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).


CONCLUSIONS
These findings suggested that multiple genetic polymorphisms of CTNNA3 may be determinants of susceptibility to TDI-induced asthma.
Kim
S-H
SH
Department of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Korea.
Cho
B-Y
BY
Park
C-S
CS
Shin
E-S
ES
Cho
E-Y
EY
Yang
E-M
EM
Kim
C-W
CW
Hong
C-S
CS
Lee
J-E
JE
Park
H-S
HS
D000328:Adult; D001249:Asthma / Q000139:chemically induced* / Q000235:genetics*; D001402:B-Lymphocytes / Q000378:metabolism; D001985:Bronchial Provocation Tests; D002461:Cell Line, Transformed; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D053539:Keratin-19 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009784:Occupational Diseases / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D014051:Toluene 2,4-Diisocyanate / Q000009:adverse effects*; D051178:alpha Catenin / Q000235:genetics*
C495273:CTNNA1 protein, human; C441963:CTNNA3 protein, human; D007074:Immunoglobulin G; D053539:Keratin-19; D051178:alpha Catenin; D014051:Toluene 2,4-Diisocyanate; D007073:Immunoglobulin E