Albuquerque R V, Hayden C M, Palmer L J, Laing I A, Rye P J, Gibson N A, Burton P R, Goldblatt J, Lesouëf P N
Department of Paediatrics, University of Western Australia, Perth, Australia.
Clin Exp Allergy. 1998 May;28(5):578-84. doi: 10.1046/j.1365-2222.1998.00273.x.
Tumour necrosis factor alpha (TNFalpha) is a potent modulator of immune and inflammatory responses, and has been implicated in a variety of autoimmune diseases, including asthma. Increased levels of TNFalpha have been detected in both sputa and bronchoalveolar lavage fluid of asthmatic subjects during acute attacks. Interindividual variation in TNFalpha levels may be genetically determined and polymorphisms within the TNF genes and nearby HLA Class II region have been associated with differences in TNFalpha production.
To investigate the association of differences in asthma-related phenotypes with two biallelic polymorphisms: a G to A substitution at position - 308 of the TNFalpha gene promoter (TNF1 and TNF2 alleles) and an NcoI polymorphism in the first intron of the lymphotoxin alpha gene (LT-alpha1 and LT-alpha2 alleles).
The regions of interest were amplified from genomic DNA using specific primers and PCR. Dot blot analysis was used for genotyping individuals for the TNFalpha - 308 polymorphism, while restriction enzyme digestion was used for genotyping individuals for the LT-alpha gene NcoI polymorphism. A case-control analysis was then performed on 74 asthmatic and 50 non-asthmatic unrelated children for each polymorphism.
The TNFalpha - 308 TNF1 allele was present at a significantly higher frequency in cases than controls (OR= 2.4, P=0.003), and homozygosity for the TNF1 allele was associated with a fivefold increased risk of physician diagnosed asthma relative to the other genotypes (OR = 5.23, P = 0.004). The LT-alpha2 allele showed similar associations, including an approximately fivefold higher risk of physician diagnosed asthma for LT-alpha2 homozygotes (OR = 4.89, P = 0.019). Evidence of a significant linear trend in asthma risk across the three genotypes was found for both polymorphisms.
These results suggest an important role for the TNFalpha gene or a linked locus in an inherited asthma diathesis.
肿瘤坏死因子α（TNFα）是免疫和炎症反应的强效调节剂，与包括哮喘在内的多种自身免疫性疾病有关。在哮喘患者急性发作期间，痰液和支气管肺泡灌洗液中均检测到TNFα水平升高。TNFα水平的个体差异可能由基因决定，TNF基因及附近的HLA II类区域内的多态性与TNFα产生的差异有关。
研究哮喘相关表型差异与两个双等位基因多态性的关联：TNFα基因启动子-308位的G到A替换（TNF1和TNF2等位基因）以及淋巴毒素α基因第一内含子中的NcoI多态性（LT-α1和LT-α2等位基因）。
使用特异性引物和聚合酶链反应（PCR）从基因组DNA中扩增感兴趣的区域。采用斑点印迹分析对个体进行TNFα - 308多态性基因分型，而使用限制性酶切对个体进行LT-α基因NcoI多态性基因分型。然后针对每种多态性，对74名哮喘儿童和50名非哮喘无关儿童进行病例对照分析。
TNFα - 308 TNF1等位基因在病例中的频率显著高于对照（比值比[OR]=2.4，P = 0.003），与其他基因型相比，TNF1等位基因纯合子患医生诊断哮喘的风险增加了五倍（OR = 5.23，P = 0.004）。LT-α2等位基因显示出类似的关联，包括LT-α2纯合子患医生诊断哮喘的风险高出约五倍（OR = 4.89，P = 0.019）。两种多态性均发现哮喘风险在三种基因型之间存在显著的线性趋势。
这些结果表明TNFα基因或一个连锁位点在遗传性哮喘素质中起重要作用。
