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A functional polymorphism in the SPINK5 gene is associated with asthma in a Chinese Han Population.

ABSTRACT: BACKGROUND: Mutation in SPINK5 causes Netherton syndrome, a rare recessive skin disease that is accompanied by severe atopic manifestations including atopic dermatitis, allergic rhinitis, asthma, high serum IgE and hypereosinophilia. Recently, single nucleotide polymorphism (SNP) of the SPINK5 was shown to be significantly associated with atopy, atopic dermatitis, asthma, and total serum IgE. In order to determine the role of the SPINK5 in the development of asthma, a case-control study including 669 asthma patients and 711 healthy controls in Han Chinese was conducted. METHODS: Using PCR-RFLP assay, we genotyped one promoter SNP, -206G>A, and four nonsynonymous SNPs, 1103A>G (Asn368Ser), 1156G>A (Asp386Asn), 1258G>A (Glu420Lys), and 2475G>T (Glu825Asp). Also, we analyzed the functional significance of -206G>A using the luciferase reporter assay and electrophoresis mobility shift assay. RESULTS: we found that the G allele at SNP -206G>A was associated with increased asthma susceptibility in our study population (p = 0.002, odds ratio 1.34, 95% confidence interval 1.11-1.60). There was no significant association between any of four nonsynonymous SNPs and asthma. The A allele at -206G>A has a significantly higher transcriptional activity than the G allele. Electrophoresis mobility shift assay also showed a significantly higher binding efficiency of nuclear protein to the A allele compared with the G allele. CONCLUSION: Our findings indicate that the -206G>A polymorphism in the SPINK5 is associated with asthma susceptibility in a Chinese Han population.

SUBMITTER: Liu Q

PROVIDER: S-EPMC2709655 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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A functional polymorphism in the SPINK5 gene is associated with asthma in a Chinese Han Population.

Liu Qiji Q Xia Yu Y Zhang Wenjing W Li Jisheng J Wang Pin P Li Huaichen H Wei Chunhua C Gong Yaoqin Y

BMC medical genetics 20090617

<h4>Background</h4>Mutation in SPINK5 causes Netherton syndrome, a rare recessive skin disease that is accompanied by severe atopic manifestations including atopic dermatitis, allergic rhinitis, asthma, high serum IgE and hypereosinophilia. Recently, single nucleotide polymorphism (SNP) of the SPINK5 was shown to be significantly associated with atopy, atopic dermatitis, asthma, and total serum IgE. In order to determine the role of the SPINK5 in the development of asthma, a case-control study i ...[more]

PMID: 19534795

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Project description:Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages. In this study, we aimed to explore the genetic factors involved in the pathogenesis of both acquired and familial type HLH.The ION TORRENT semi-conductor sequencing method was used to sequence samples from 10 patients who were diagnosed or highly suspected of HLH. Then SNP rs2303116 of STXBP2 genotyping was performed by Sanger sequencing method on samples from 24 patients with HLH and 182 normal controls. Genotype frequencies were then compared and tested by multivariate logistic regression. Finally, the potential impact of rs2303116 on splicing factor binding ability was evaluated using the ESEfinder 3.0 online tool.A total of 92 variants were identified in 10 HLH patients, of which 24 variants were rare variants (MAF<0.01), while the remaining 68 variants were common variants (MAF>0.01). Among them, 8 different genetic variations in the STXBP2 sequence were identified. We focused on the synonymous SNP rs2303116, as 30% of patients had CT/TT genotype. SNP genotyping was further performed on 24 HLH patients and 182 healthy control cohorts, and the results indicated a significantly elevated CT/TT genotype frequency of rs2303116 in HLH patients compared with healthy controls (patients 37.5% VS. controls 13.2%, P = 0.009, OR = 3.900, 95% CI 1.537-9.899). Multivariate logistic regression analysis indicated that being female (OR 0.350, 95% CI 0.143-0.861, P = 0.018) and of an older age (>43y, OR 0.312, 95% CI 0.118-0.822, P = 0.014) were independent protective factors, and the rs2303116 CT/TTgenotype (OR 3.900, 95% CI 1.537-9.899, P = 0.009) was an independent risk factor for HLH pathogenesis. By comparing the clinical parameters between HLH patients with CT/TT and CCgenotypes, we found that the patients with CT/TT genotype had significantly lower levels of fibrinogen, indicating more aggravated macrophage activation. In silico analysis of splice factor binding to rs2303116 CT/TT genotypes showed significant decrease for SRSF1 but increase for SRSF6, which suggested abnormal splicing machinery was associated with HLH pathogenesis.Our study demonstrated for the first time that HLH patients had significantly higher frequencies of the STXBP2 gene polymorphism rs2303116 variant compared with a healthy Chinese Han population, through clinical comparisons and further predictions we suggested regulation of alternative splicing by alleles of SNP rs2303116 could be involved in HLH pathogenesis.

Dataset Information

A functional polymorphism in the SPINK5 gene is associated with asthma in a Chinese Han Population.

Publications

A functional polymorphism in the SPINK5 gene is associated with asthma in a Chinese Han Population.

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