Genetic polymorphisms at FCER1B and PAI-1 and asthma susceptibility

Background We previously detected a promoter polymorphism (-109C/T) in the gene for the beta-chain of the high-affinity receptor for IgE (FCER1B), which was associated with total serum IgE levels but not with asthma in a Japanese population. A genetic interaction is biologically plausible between Fc epsilon RI-beta and the plasminogen activator inhibitor 1 (PAI-1), which is highly expressed in mast cells in asthmatics and plays an essential role in airway remodelling. We hypothesized that FCER1B promoter polymorphisms, by modifying the intensity of mast cell activation signals, modulate the genetic effects of a functional 4G/5G polymorphism in the PAI-1 gene on asthma. Objective To examine whether FCER1B promoter polymorphisms (-109C/T and -654C/T) influence the genetic effects of the functional polymorphism (4G/5G) at the PAI-1 promoter region on asthma susceptibility using a case-control analysis. Methods Subjects (374 asthmatic patients and 374 non-asthmatic controls) were divided into combined genotype groups based on the presence of FCER1B-109TT and -654CC genotypes and the PAI-1 4G allele. Logistic regression analysis was used to estimate adjusted odds ratios for asthma associated with the different genotype groups. Results Individuals homozygous for the FCER1B-109T/-654C haplotype and the PAI-1 5G allele had a reduced susceptibility to asthma; the odds ratio for the development of asthma was 0.20 (95% confidence interval, 0.084-0.46; P=0.00015) for them, compared with individuals also homozygous for the -109T/-654C haplotype at FCER1B but carrying the 4G allele at PAI-1. The regression model also showed an interaction of the PAI-1 4G/5G genotype with the FCER1B-109C/T (P for interaction=0.0017) or FCER1B-654C/T (P for interaction=0.031) on asthma. Conclusions The present findings suggest a synergistic interaction between FCER1B and PAI-1 genes in asthma susceptibility.