Association between a sequence variant in the IL-4 gene promoter and FEV1 in asthma

Recent family-based studies have revealed evidence for linkage of human chr omosome 5q31 to the diagnosis of asthma, elevated serum IgE levels, and bro nchial hyperresponsiveness. Among the candidate genes in this region is the gene encoding for human interleukin-4 (IL-4). We reasoned that this gene c ould also serve as a candidate gene with respect to asthma severity as indi cated by the FEV, measured when bronchodilator treatment was withheld. To t est this hypothesis, we examined a large population of patients with asthma (ascertained without respect to genetic characteristics), for associations between a genetic variant in the IL-4 promoter region (C-589T) and asthma severity, as indicated by FEV1. We used amplification by the polymerase cha in reaction followed by BsmF1 restriction digestion to assign genotypes at the IL-4 promoter C-589T locus. We compared genotypes at this locus in 772 Caucasian and African American patients with asthma of varying severity, an d we used multiple regression analysis to relate genotypic findings to FEV, . Among white individuals, the homozygous presence of the C-589T IL-4 promo ter genotype (TT) was associated with a FEV1 below 50% of predicted (p = 0. 013; OR, 1.44; 95% CI: 1.09 to 1.90). Subjects with the TT genotype had mea n FEV1 (% predicted) values 4.5% lower than those of subjects with the wild -type (CC) genotype at this locus. FEV, values of white patients with a CC or CT genotype were broadly distributed, whereas the TF genotype was associ ated with a narrow distribution of low FEV, values. The frequency of the T allele was significantly greater (p = 1 x 10(-23)) among African American a sthmatics (0.544) than among white asthmatics (0.183). These data provide t he first evidence associating FEV1 in patients with asthma and genetic dete rminants at any locus. Our data are consistent with the idea that the FEV1 in asthma is the result of multiple factors; one of these factors is the ge notype at the IL-4 C-589T locus. This locus is associated with a small but significant decrement in pulmonary function among white asthmatic subjects.