Tumor necrosis factor alpha polymorphism associated with increased susceptibility to development of adult T-cell leukemia/lymphoma in human T-lymphotropic virus type 1 carriers.
Tumor necrosis factor alpha polymorphism associated with increased susceptibility to development of adult T-cell leukemia/lymphoma in human T-lymphotropic virus type 1 carriers.
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发表时间：
2001
期刊：
影响因子：
11.2
通讯作者：
K. Tsukasaki;C. W. Miller;T. Kubota;S. Takeuchi;T. Fujimoto;S. Ikeda;M. Tomonaga;H. Koeffler-H.-K
中科院分区：
文献类型：
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作者：
K. Tsukasaki;C. W. Miller;T. Kubota;S. Takeuchi;T. Fujimoto;S. Ikeda;M. Tomonaga;H. Koeffler-H.-K
人类嗜T淋巴细胞病毒1型（HTLV-1）在病因学上与成人T细胞白血病/淋巴瘤（ATL）相关。然而，大多数感染HTLV-1的个体不会发生ATL。为了试图确定促进ATL进展的遗传因素，我们在HTLV-1携带者中研究了ATL易感性与几种多态性之间的关系：GSTM 1、GSTT 1和CYP 1A 1中的三种“减少解毒”多态性，BCL 2中的“促凋亡”多态性，以及肿瘤坏死因子α（TNF-α）中的五种“高产”多态性，使用基于PCR的基因分型测定。ATL患者（n = 71）比HTLV-1携带者年轻（n = 80; 57 +/- 12 vs 63 +/- 10岁; P = 0.0017）。ATL患者的男女比例高于携带者（分别为52：19和19：61; P < 0.0001），可能反映了女性中HTLV-1感染的发生率较高，男性中ATL的发生率较高。我们发现与TNF-α基因启动子/增强子区域的高转录活性相关的TNF-α-857 T等位基因的频率在ATL个体中比健康携带者更高（分别为18.3%和8.8%;比值比为2.34; 95%置信区间为1.2-4.7）。其他四种TNF-α多态性均不是ATL发展风险的重要指标，尽管所有TNF-α多态性的比值比（ATL与携带者）均高于1.0。此外，对GSTM 1、GSTT 1、CYP 1A 1和BCL 2的多态性分析显示，ATL患者与健康携带者之间没有显着差异。导致TNF-α产生增加的遗传多态性可能会增加HTLV-1携带者对ATL的易感性。或者，但不太可能，HLA基因座可能是一个重要因素，因为TNF-α基因位于MHC的III类区域内;然而，857 T等位基因与ATL发展相关的HLA等位基因不连锁不平衡。
Human T-lymphotropic virus type 1 (HTLV-1) is etiologically associated with adult T-cell leukemia/lymphoma (ATL). Nevertheless, most individuals infected with HTLV-1 do not develop ATL. To attempt to identify genetic factors promoting the progression to ATL, we investigated in HTLV-1 carriers the relationship between susceptibility to ATL and several polymorphisms: the three "decreased-detoxifying" polymorphisms in GSTM1, GSTT1, and CYP1A1, the "proapoptotic" polymorphism in BCL2, and the five "high-production" polymorphisms in tumor necrosis factor alpha (TNF-alpha) using PCR-based genotyping assays. ATL patients (n = 71) were younger than HTLV-1 carriers (n = 80; 57 +/- 12 versus 63 +/- 10 years; P = 0.0017). MALE:female ratio in ATL patients was higher than in carriers (52:19 versus 19:61, respectively; P < 0.0001), probably reflecting a higher incidence of HTLV-1 infection in females and a higher incidence of development of ATL in males. We found that the frequency of the TNF-alpha-857T allele, reported to be associated with high transcriptional activity of the promoter/enhancer region of the TNF-alpha gene, was enriched in individuals with ATL compared with healthy carriers (18.3% versus 8.8%, respectively; odds ratio, 2.34; 95% confidence interval, 1.2-4.7). None of the other four TNF-alpha polymorphisms was a significant indicator of risk of development of ATL, although odds ratios (ATL versus carrier) of all of the TNF-alpha polymorphisms were higher than 1.0. Furthermore, analysis of polymorphisms for GSTM1, GSTT1, CYP1A1, and BCL2 showed no significant difference between ATL patients and healthy carriers. Genetic polymorphism leading to increased TNF-alpha production may enhance susceptibility to ATL among HTLV-1 carriers. Alternatively, but less likely, the HLA loci might be an important factor because the TNF-alpha gene lies within the class III region of the MHC; however, the 857T allele is not in linkage disequilibrium with HLA alleles associated with ATL development.