A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children

Background: Increased levels of total serum IgE are a strong risk factor for the development of asthma. IgE is also involved in host defenses against parasites and fungi. Linkage of total serum IgE with markers located close to the 3 Mb cluster of cytokine genes in chromosome 5q31 has been reported. IL-4 or IL-13 are regarded as essential for IgE synthesis. Objective: We tested whether polymorphisms in the IL-13 gene might explain the linkage between chromosome 5q31 and total serum IgE levels. Methods: We used denaturing HPLC to detect polymorphisms in overlapping PCR fragments of the IL-13 gene including promoter and 3' untranslated regions. After sequencing was performed to identify the locations of the polymorphisms, PCR and primer- induced restriction site assays were used to genotype subjects in 3 unselected populations. Results: We report here 7 polymorphisms (6 novel) in IL-13. Four of these polymorphisms are tightly linked to a variant in the terminal portion of the coding region of the gene that results in a predicted amino acid change in residue 130 (Arg130Gln). The Gln form is strongly associated (P = .000002) with increased serum IgE levels in 3 different populations comprising a total of 1399 children. Two additional polymorphisms in the promoter region of IL-13 are more loosely linked to Arg130Gln and are also less significantly associated with total serum IgE levels. Conclusion: These data suggest that the Arg130Gln polymorphism in IL-13, or others in close linkage with it, is associated with the development of the elevated serum IgE phenotype.