Sharma Shilpy, Sharma Amit, Kumar Sarvesh, Sharma Surendra K, Ghosh Balaram
Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi-110007, India.
Am J Respir Cell Mol Biol. 2006 Oct;35(4):488-95. doi: 10.1165/rcmb.2006-0084OC. Epub 2006 May 25.
Both biochemical and genetic evidence have implicated the genes for TNF-alpha (TNFA) and lymphotoxin-alpha (LTA) in atopic asthma. Here, we report for the first time the association of their genotypes and haplotypes with atopic asthma in Indian populations. We genotyped seven single nucleotide polymorphisms, encompassing the two genes, in patients and control subjects in two independent cohorts. Serum TNF-alpha levels of selected individuals were measured and correlated with genotypes and haplotypes. The A allele of the TNFA-863C > A polymorphism was associated with reduced risk of asthma (P = 0.002 and 0.007 in Cohorts A and B, respectively), reduced TsIgE levels (P = 0.0024 and P = 0.0029 in Cohorts A and B, respectively), and reduced serum TNF-alpha levels (P < 0.05). A marginal association was also observed for LTA_NcoI polymorphism with asthma and TsIgE levels. Furthermore, analysis using HAPLO. STATS showed significant differences in the major haplotype frequencies (> 3%) between patients and control subjects (P = 0.002 and P = 0.006 for Cohorts A and B, respectively). Individually, the haplotype GATCCG was the most frequent in patients (P = 0.0029 and P = 0.0025 for Cohorts A and B, respectively), and was associated with high TsIgE and serum TNF-alpha levels, whereas AACACG was the most frequent in the control subjects (P = 0.0032 and P = 0.022 for Cohorts A and B, respectively), and was associated with low TsIgE and serum TNF-alpha levels. We also report here that the C > A substitution at position -863 of the TNFA influences the binding of nuclear proteins in electrophoretic mobility shift assay experiments. Thus, the TNFA-863C > A polymorphism in the promoter region of TNFA may influence TNF-alpha expression and affect TsIgE levels and susceptibility to asthma.
生化和遗传学证据均表明，肿瘤坏死因子-α（TNFA）基因和淋巴毒素-α（LTA）基因与特应性哮喘有关。在此，我们首次报告了它们的基因型和单倍型与印度人群特应性哮喘的关联。我们在两个独立队列的患者和对照受试者中对包含这两个基因的7个单核苷酸多态性进行了基因分型。测量了选定个体的血清肿瘤坏死因子-α水平，并将其与基因型和单倍型进行关联分析。TNFA - 863C>A多态性的A等位基因与哮喘风险降低相关（队列A和B中P值分别为0.002和0.007），总IgE水平降低（队列A和B中P值分别为0.0024和0.0029），血清肿瘤坏死因子-α水平降低（P<0.05）。LTA_NcoI多态性与哮喘和总IgE水平也存在边缘关联。此外，使用HAPLO.STATS分析显示，患者和对照受试者之间主要单倍型频率（>3%）存在显著差异（队列A和B中P值分别为0.002和0.006）。单独来看，单倍型GATCCG在患者中最为常见（队列A和B中P值分别为0.0029和0.0025），并与高总IgE和血清肿瘤坏死因子-α水平相关，而AACACG在对照受试者中最为常见（队列A和B中P值分别为0.0032和0.022），并与低总IgE和血清肿瘤坏死因子-α水平相关。我们在此还报告，在电泳迁移率变动分析实验中，TNFA基因-863位的C>A替换会影响核蛋白的结合。因此，TNFA启动子区域的TNFA - 863C>A多态性可能会影响肿瘤坏死因子-α的表达，并影响总IgE水平和哮喘易感性。
