Genes of the IL-I family encode three different peptides, IL-1 alpha, IL-1 beta, and IL-1Ra, respectively. IL-1 operates through IL-1RI, and is involved in airway inflammation in asthmatic subjects, whereas IL-1Ra appears to be a specific competitive inhibitor of IL-I. All genes are on chromosome 2q12-21 where genomewide searches have identified linkage for asthma. To test whether variants of IL-1 relate to asthma, we conducted a genetic association study in a Japanese population. We show that the A2 allele of IL1RN (encoding IL-1Ra) associates with nonatopic asthma [OR = 5.71, 95% CI: 1.63-19.8, Pc = 0.007]. Both atopic and nonatopic asthmatics with the A2 allele had significantly lower serum IL-1Ra levels in both types of asthmatics. Peripheral blood cells from asthmatics with A2 alleles, however, produced as much IL-1 as did those with Al homozygotes. Since Th1 and Th2 cytokines differentially regulate the ratio between IL-1 beta and IL-1Ra, these findings suggest that dysregulation of IL-1 beta/IL-1Ra, probably due to interaction between epithelium and immune-competent cells in the airway, is important in asthma inflammation.