The R576 IL-4 receptor alpha allele correlates with asthma severity.

BACKGROUND: Atopic disorders, including asthma, are very prevalent, affecting up to 40% of populations, and their incidence is on the rise. Although environmental factors are important in the development of atopy, there is a strong genetic predisposition. Several genes and chromosomal regions have been linked to atopy and asthma, supporting the polygenic nature of these disorders. IL-4 and IL-13 are T(H)2 cytokines with numerous activities that contribute to allergic inflammation and asthma. Both IL-4 and IL-13 use the IL-4 receptor alpha chain (IL-4Ralpha) as a component of their respective receptor systems. Allelic variants of IL-4Ralpha have been reported, and the R576IL-4Ralpha allele was recently shown to be a risk factor for atopy. OBJECTIVE: We sought to determine whether the R576 allele was associated with the prevalence or clinical severity of asthma. METHODS: We developed a rapid, reliable, PCR-based assay to screen individuals for the R576IL-4Ralpha allele and used this assay to genotype prospectively recruited individuals with asthma (n = 149) and control subjects (n = 57). RESULTS: There was a strong association of R576IL-4Ralpha with the prevalence and clinical severity of asthma. In a prospective cohort, homozygosity for R576 was significantly increased in individuals with asthma (n = 149, P =.03; relative risk 8.2) compared with controls (n = 57). Furthermore, 1 or 2 copies R576IL-4Ralpha correlated with asthma severity establishing a genotype-phenotype relationship and suggesting a gene dosage effect. CONCLUSIONS: Thus R576IL-4Ralpha acts as an allergic asthma susceptibility and disease-modifying gene and may serve as a clinically useful marker of asthma severity.