Amino-acid substitutions in the IKAP gene product significantly increase risk for bronchial asthma in children

The complex etiology of bronchial asthma (BA), one of the most common infla mmatory diseases throughout the world, involves a combination of various ge netic and environmental factors. A number of investigators have undertaken linkage and association studies to shed light on the genetic background of BA, but the genetic aspects of this disease are still poorly understood. In the course of a project to screen the entire human genome for single nucle otide polymorphisms (SNPs) that might represent useful markers for large-sc ale association analyses of common diseases and pharmacogenetic traits, we identified six SNPs within the gene encoding I-kappaB-associated protein (I KAP), a regulator of the NF-kappaB signal pathway. Most of these SNPs were in linkage disequilibrium with each other. We observed a strong allelic ass ociation between BA in childhood and two of the SNP sites, T3214A (Cys1072S er) and C3473T (Pro1158Leu); P = 0.000004 for T3214A and P = 0.0009 for C34 73T. T3214A was also associated with BA in adult patients (P = 0.000002), b ut C3473T was not (P = 0.056). To confirm the above results, we compared es timated frequencies of haplotypes of the six SNPs between BA patients and c ontrols. We found a strong association between BA in childhood and a specif ic haplotype, TGAAAT, that involved two amino-acid substitutions (819T, 229 5G, 2446A, 2490A, 3214A, and 3473T; P = 0.00004, odds ratio, 2.94; 95% conf idence interval [CI], 2.48-3.4). On the other hand, haplotype TACGTC, which differed from the TGAAAT haplotype in the last five nucleotides, was inver sely correlated with the BA phenotype (P = 0.002; odds ratio, 9.83; 95% CI, 8.35-11.31). These results indicated that specific variants of the IKAP ge ne, or a variant in linkage disequilibrium with the TGAAAT haplotype, might be associated with mechanisms responsible for early-onset BA.