Genetic Variation in Surfactant Protein-A2 Results in Altered Regulation of Eosinophil Activities and Enhanced Eosinophilia in Patients with Asthma

Humans express a repertoire of single amino acid genetic variant proteins for surfactant protein (SP)-A1 and SP-A2 that may be associated with certain lung physiology and disease. We have previously shown that SP-A mediates eosinophil degranulation and that certain allelic variants of SP-A2 are dysfunctional in asthma. We therefore hypothesized that variation in SP-A2 at position Gln(Q)223Lys(K) leads to altered regulation of eosinophil activities and that patients with asthma who harbor the minor allele may demonstrate enhanced eosinophilia. SP-A was extracted from the lavage of patients with alveolar proteinosis and genotyped for the SP-A2 223Q/K locus. Genotyped SP-A was incubated with eosinophils in vitro to assess regulation of eosinophil activity. Humanized SP-A transgenic mice were created that represent single allelic variant changes in SP-A2 protein, designated SP-A2 223Q and SP-A2 223K. Humanized mice were challenged in an allergic model to determine the effect of SP-A genetic variation during allergic inflammation. We discovered that SP-A2 223Q inhibits eosinophil degranulation and leads to reduced viability of eosinophils in culture conditions. In contrast, SP-A2 223K is unable to attenuate eosinophil degranulation and has no effect on eosinophil viability. Humanized SP-A2 223Q mice have significantly reduced mucus production in an allergic model compared with SP-A^−/− mice, whereas mice expressing SP-A2 223K were not different from mice that are devoid of SP-A. Additionally, from genotyped samples obtained from subjects with mild to moderate asthma, we discovered that subjects with asthma harboring one or more copies of the minor allele (223K) had a greater percentage of eosinophils in their bronchoalveolar lavage and serum. These studies suggest that genetic variation in SP-A2 at position SP-A2 Gln223Lys is an important mediator of eosinophil activities, which may lead to a more severe asthma phenotype.