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 chromosome 5q31 to the diagnosis of asthma, elevated serum IgE levels, and bronchial hyperresponsiveness. Among the candidate genes in this region is the gene encoding for human interleukin-4 (IL-4). We reasoned that this gene could also serve as a candidate gene with respect to asthma severity as indicated by the FEV₁ measured when bronchodilator treatment was withheld. To test 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 chain 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, and we used multiple regression analysis to relate genotypic findings to FEV₁. Among white individuals, the homozygous presence of the C- 589T IL-4 promoter 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 mean FEV₁ (% predicted) values 4.5% lower than those of subjects with the wild-type (CC) genotype at this locus. FEV₁ values of white patients with a CC or CT genotype were broadly distributed, whereas the TT genotype was associated with a narrow distribution of low FEV₁ values. The frequency of the T allele was significantly greater (p = 1 x 10^-23) among African American asthmatics (0.544) than among white asthmatics (0.183). These data provide the first evidence associating FEV₁ in patients with asthma and genetic determinants 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 genotype at the IL-4 C-589T locus. This locus is associated with a small but significant decrement in pulmonary function among white asthmatic subjects.