Abstract
Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) promotes the apoptosis of eosinophils and inhibits FcɛRI-dependent mediator release from mast cells. We investigated the genetic association between sequence variants in Siglec-8 and diagnosis of asthma, total levels of serum IgE (tIgE), and diagnosis of eosinophilic esophagitis (EE) in diverse populations. The effect of sequence variants on Siglec-8 glycan ligand-binding activity was also examined. Significant association with asthma was observed for SNP rs36498 (odds ratios (OR), 0.69, P=8.8 × 10−5) among African Americans and for SNP rs10409962 (Ser/Pro) in the Japanese population (OR, 0.69, P=0.019). Supporting this finding, we observed association between SNP rs36498 and current asthma among Brazilian families (P=0.013). Significant association with tIgE was observed for SNP rs6509541 among African Americans (P=0.016), and replicated among the Brazilian families (P=0.02). In contrast, no association was observed with EE in Caucasians. By using a synthetic polymer decorated with 6′-sulfo-sLex, a known Siglec-8 glycan ligand, we did not find any differences between the ligand-binding activity of HEK293 cells stably transfected with the rs10409962 risk allele or the WT allele. However, our association results suggest that the Siglec8 gene may be a susceptibility locus for asthma.
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Acknowledgements
Funding source: This work was supported by a Dana Foundation Human Immunology Consortium grant; National Institutes of Health (NIH) grants HL087699, HL49612, AI50024, AI44840, HL075417, HL072433, AI72265, AI41040, ES09606, HL072433, and RR03048; and EPA grant 83213901; as well as by Glaxo-Smith-Kline (project WE445 entitled ‘Immunogenetics of Schistosomiasis and Asthma’). KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program at Johns Hopkins. BSB was supported in part as a Cosner Scholar in Translational Research at Johns Hopkins. RAM was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. LFZ was supported partially by the National Natural Science Foundation of China (30400191 and 30570797) and Jiangsu Key Principal Investigator of Medicine (RC2007043). We thank all the volunteers for generous participation in this study. We thank Deguang Mu of the Fourth Military Medical University, PR China. We thank Tracey Hand and Monica Campbell of the Johns Hopkins Bayview Genetics Research Facility, and Patricia Oldewurtel, Johns Hopkins University, for technical support. We thank Dr Bovin of the Russian Academy of Sciences, Moscow, Russia, for the polymer 6′-sulfo-sLex. We thank Dr Yukiko Maeda for help with genotyping of the Japanese sample.
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Gao, PS., Shimizu, K., Grant, A. et al. Polymorphisms in the sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) gene are associated with susceptibility to asthma. Eur J Hum Genet 18, 713–719 (2010). https://doi.org/10.1038/ejhg.2009.239
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DOI: https://doi.org/10.1038/ejhg.2009.239
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