This variant, formerly titled ATOPY, SUSCEPTIBILITY TO, has been reclassified as a polymorphism. Hamosh (2023) noted that the S503P variant was present in 46,670 of 282,530 alleles and in 4,585 homozygotes in the gnomAD database, with an allele frequency of 0.1652.
In an association study of individuals aged 6 to 22 years from 109 nuclear families, Kruse et al. (1999) found significantly reduced total IgE concentrations (147050) in individuals with a ser503-to-pro (S503P) polymorphism in IL4R. Kruse et al. (1999) also found that S503P is in direct linkage disequilibrium with another polymorphism, Q576R (147781.0001), with 76% of R576 carriers also carrying P503, and 95% of P503 carriers also carrying R576. The R576 allele was also associated with significantly reduced IgE levels, and the most significant result occurred with carriers of both P503 and R576 (p = 0.0008). R576 and P503 were not associated with specific sensitization to common inhalant allergens. Functional studies suggested that the S503P and Q576R polymorphisms independently reduce STAT6 (601512) binding and STAT6 phosphorylation, leading to reduced total IgE levels. In addition, the occurrence of both polymorphisms together, but not alone, increases IRS (see 147545) phosphorylation, leading to an even greater reduction in total IgE levels. (Because the common allele, S503, is associated with atopy susceptibility, the minor allele, P503, can be viewed as conferring atopy resistance.)
Howard et al. (2002) investigated 5 IL4RA single-nucleotide polymorphisms in a population of Dutch families ascertained through a proband with asthma (600807). They observed significant associations of atopy and asthma-related phenotypes with several IL4RA polymorphisms, including the common allele of S503P, which they referred to as SER478PRO (S478P), and total serum IgE levels. A significant gene-gene interaction between the common allele of S503P in IL4RA and the rare allele of the -1112C-T promoter variant (147683.0001) in IL13, previously shown to be associated with bronchial hyperresponsiveness, was detected. Individuals with the risk genotype for both genes were at almost 5 times greater risk for the development of asthma compared to individuals with both nonrisk genotypes.
Franjkovic et al. (2005) found that transfection of a mouse T-cell line with human IL4R containing the S503P variant did not influence IL4-induced T-cell proliferation compared with wildtype IL4R. Analysis of 6 common IL4R coding SNPs, including Q576R and S503P, and common haplotypes in 300 blood donors failed to show a significant association with elevated serum IgE level. Moreover, analysis of the 3 most informative coding SNPs and related 2- and 3-point haplotypes in a second group of 689 blood donors failed to detect a significant association with elevated serum IgE. Franjkovic et al. (2005) concluded that common coding SNPs in IL4R are unlikely to contribute significantly to elevated IgE levels.
