Polymorphisms in the Sialic Acid-binding Immunoglobulin-like lectin 8 (SIGLEC8) Gene Are Associated with Asthma in Two Populations.

RATIONALE: Siglec-8 may play a role in promoting apoptosis of eosinophils and inhibiting FcɛRI-dependent mediator release from mast cells. We investigated the genetic association of sequence variants in the Siglec-8 gene with asthma and associated phenotypes.METHODS: Seven single nucleotide polymorphisms (SNPs) in Siglec-8 were genotyped in 344 African American subjects, and two of them were replicated in 955 Japanese individuals consisting of 486 asthmatics and 469 healthy controls. Gene constructs containing wild type and the risk allele were generated and then transfected into HEK293 cells to test the effect of the polymorphism on Siglec-8 ligand binding activity.RESULTS: Significant association was observed for the SNP rs10409962 Ser/Pro (odds ratio (OR), 0.48, P = 0.039), and rs3829659 (OR, 0.40, 0.01) and risk of asthma in the case-control study of the African American population. This association was further substantiated by haplotype analysis (P = 0.003). The SNP rs10409962, but not rs3829659, was also associated with asthma in the Japanese population (OR, 0.73, P = 0.032). Since SNP rs10409962 is located near the carbohydrate binding domain of Siglec-8, we performed Siglec-8 ligand binding assays using flow cytometry and we failed to observe any clear differences in glycan ligand binding activity in cells transfected with the SNP rs10409962 risk allele compared to the wild type allele.CONCLUSIONS: These results suggest that the SIGLEC8 gene is an important susceptibility locus for asthma. The SNP rs10409962 may confer protection against asthma. Further study is needed to validate these findings. RATIONALE: Siglec-8 may play a role in promoting apoptosis of eosinophils and inhibiting FcɛRI-dependent mediator release from mast cells. We investigated the genetic association of sequence variants in the Siglec-8 gene with asthma and associated phenotypes. METHODS: Seven single nucleotide polymorphisms (SNPs) in Siglec-8 were genotyped in 344 African American subjects, and two of them were replicated in 955 Japanese individuals consisting of 486 asthmatics and 469 healthy controls. Gene constructs containing wild type and the risk allele were generated and then transfected into HEK293 cells to test the effect of the polymorphism on Siglec-8 ligand binding activity. RESULTS: Significant association was observed for the SNP rs10409962 Ser/Pro (odds ratio (OR), 0.48, P = 0.039), and rs3829659 (OR, 0.40, 0.01) and risk of asthma in the case-control study of the African American population. This association was further substantiated by haplotype analysis (P = 0.003). The SNP rs10409962, but not rs3829659, was also associated with asthma in the Japanese population (OR, 0.73, P = 0.032). Since SNP rs10409962 is located near the carbohydrate binding domain of Siglec-8, we performed Siglec-8 ligand binding assays using flow cytometry and we failed to observe any clear differences in glycan ligand binding activity in cells transfected with the SNP rs10409962 risk allele compared to the wild type allele. CONCLUSIONS: These results suggest that the SIGLEC8 gene is an important susceptibility locus for asthma. The SNP rs10409962 may confer protection against asthma. Further study is needed to validate these findings.