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Am. J. Respir. Crit. Care Med., Volume 160, Number 3, September 1999, 919-922

Association Between a Sequence Variant in the IL-4 Gene Promoter and FEV1 in Asthma

ESTEBAN G. BURCHARD, EDWIN K. SILVERMAN, LANNY J. ROSENWASSER, LARRY BORISH, CHANDRI YANDAVA, ANTHONY PILLARI, SCOTT T. WEISS, JEFFREY HASDAY, CRAIG M. LILLY, JEAN G. FORD, and JEFFREY M. DRAZEN

Pulmonary and Critical Care Division and Channing Laboratory, Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; National Jewish Medical and Research Center, Denver, Colorado; University of Maryland, Baltimore, Maryland; and Harlem Hospital Center, Columbia University, New York, New York

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 × 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.




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