Kim S-H, Ye Y-M, Lee S-K, Choi J-H, Holloway J W, Park C-S, Park H-S
Department of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Korea.
Clin Exp Allergy. 2006 Oct;36(10):1247-53. doi: 10.1111/j.1365-2222.2006.02567.x.
We speculated TNF-alpha can be one of candidate gene for aspirin-intolerant asthma (AIA) because TNF-alpha is pro-inflammatory cytokine and known to be increased level in asthmatic airways. In addition, genetic interaction between TNF-alpha and human antigen leucocyte (HLA) DPB1*0301, which is a strong genetic marker for AIA, was examined for its close location within chromosome 6.
To investigate genetic association of TNF-alpha with an AIA phenotype, three study groups (163 patients with AIA, 197 patients with aspirin-tolerant asthma (ATA), 257 normal control subjects) were enrolled. Single nucleotide polymorphisms (SNPs) were genotyped using a single-base extension method and HLA DPB1 genotyping was determined by high-throughput sequencing method.
All five SNPs of TNF-alpha were tested; there were no significant differences in allele and genotype frequencies among the three groups. However, significant association between TNF-alpha-308G>A polymorphism and atopy status was noted (P<0.05). Gene to gene interaction between TNF-alpha-1031T>C (or -863C>A or -857C>A) and HLA DPB1*0301could synergistically increase the susceptibility to AIA with odds ratio (OR) to 7.738 (or OR=8.184 for -863C>A, OR=7.500 for -857C>T, P<0.001, respectively).
TNF-alpha promoter polymorphism may significantly increase susceptibility to AIA by gene-to-gene interaction with HLA DPB1*0301.
我们推测肿瘤坏死因子-α（TNF-α）可能是阿司匹林不耐受性哮喘（AIA）的候选基因之一，因为TNF-α是一种促炎细胞因子，且已知在哮喘气道中水平会升高。此外，还研究了TNF-α与人类白细胞抗原（HLA）DPB10301之间的基因相互作用，HLA DPB10301是AIA的一个强遗传标记，因其在6号染色体内位置相邻。
为研究TNF-α与AIA表型的遗传关联，招募了三个研究组（163例AIA患者、197例阿司匹林耐受型哮喘（ATA）患者、257名正常对照受试者）。使用单碱基延伸法对单核苷酸多态性（SNP）进行基因分型，通过高通量测序法确定HLA DPB1基因分型。
对TNF-α的所有五个SNP进行了检测；三组之间的等位基因和基因型频率无显著差异。然而，注意到TNF-α -308G>A多态性与特应性状态之间存在显著关联（P<0.05）。TNF-α -1031T>C（或-863C>A或-857C>A）与HLA DPB1*0301之间的基因相互作用可协同增加AIA易感性，比值比（OR）为7.738（-863C>A时OR = 8.184，-857C>T时OR = 7.500，P均<0.001）。
TNF-α启动子多态性可能通过与HLA DPB1*0301的基因相互作用显著增加AIA易感性。
