Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations

Abstract

After a genomewide screen in the Hutterites was completed, the IL4RA gene was examined as the 16p-linked susceptibility locus for asthma and atopy. Seven known variants and one novel variant, representing all nonsynonymous substitutions in the mature protein, were examined in the Hutterites; on the basis of studies in the Hutterites, outbred white, black, and Hispanic families were genotyped for selected markers. All population samples showed evidence of association to atopy or to asthma (P values.039-.0044 for atopy and. 029-.0000061 for asthma), but the alleles or haplotypes showing the strongest evidence differed between the groups. Overall, these data suggest that the IL4RA gene is an atopy- and asthma-susceptibility locus but that variation outside the coding region of the gene influences susceptibility.

Figure 1

Genomic organization of the IL4RA gene on chromosome 16p12 (not drawn to scale). The genomic organization of the gene was determined from the genomic (GenBank accession number AC004525) and cDNA sequences (Idzerda et al. 1990). Exons (E1–E9) are shown as rectangles, and introns (I1–I8) are shown as broken horizontal lines. The sizes of the exons and introns are as follows: E1, 70 bp; E2, 39 bp; E3, 152 bp; E4, 152 bp; E5, 157 bp; E6, 100 bp; E7, 79 bp; E8, 50 bp; E9, 1,579 bp; I1, 1,847 bp; I2, 2,609 bp; I3, 1,446 bp; I4, 5,920 bp; I5, 3,111 bp; I6, 3,007 bp; I7, 1,768 bp; and I8, 1,436 bp. Amino acid polymorphisms in the mature protein are shown. The polymorphism at amino acid 727 was reported in this study; others are from Deichmann and colleagues (Kruse et al. ; Deichmann et al. 1997) and Hershey et al. (1997).