Densem C G, Hutchinson I V, Yonan N, Brooks N H
Cardiothoracic Transplant Unit, Wythenshawe Hospital, United Kingdom, Manchester, UK.
J Heart Lung Transplant. 2001 Dec;20(12):1265-73. doi: 10.1016/s1053-2498(01)00358-8.
Tumor necrosis factor-alpha (TNF-alpha) has been implicated in cardiovascular disease. Polymorphism of the TNF-alpha gene promoter region (position -308) influences an individual's production of TNF-alpha. This affects susceptibility to acute rejection after cardiac transplantation. Because the highest serum levels of TNF-alpha have been found in recipients with cardiac transplant vasculopathy and because TNF-alpha blockade can prevent the disease in rabbits, we investigated the effect of TNF-alpha promoter polymorphism on the development of vasculopathy in human cardiac allograft recipients.
Using sequence-specific primers to the TNF-alpha gene and polymerase chain reaction, the genotypes of 147 cardiac transplant recipients and 134 heart donors were identified. An association was sought between the presence of high-producing (A homozygotes, GA heterozygotes) or low-producing (G homozygotes) TNF-alpha genotype and the development of coronary vasculopathy, diagnosed by routine surveillance coronary angiography.
We found that 31.9% of recipients and 27.0% of donors were high TNF-alpha producers. The presence of the high-producing TNF-alpha allele led to an earlier diagnosis of vasculopathy; 3.42 years (+/- 91.3 days) vs 3.84 years (+/- 76.3 days) for high- and low-producing cardiac graft recipients, respectively; 3.52 years (+/- 87.3 days) vs 3.78 years (+/- 77.4 days) for high- and low-producing donor grafts, respectively. However, neither of these differences were significant. By Kaplan Meier actuarial analysis and log-rank test, TNF-alpha polymorphism had no effect on the freedom from vasculopathy when considering either recipient (p = 0.99) or donor (p = 0.86) TNF-alpha genotype. Multivariate analysis identified increasing donor age and the number of acute rejection episodes of International Society for Heart and Lung Transplantation grade 3 or greater as independent risk factors for vasculopathy in both the recipient and donor cohorts.
Polymorphism at position -308 in the promoter region of the TNF-alpha gene fails to predict the development of cardiac transplant-related vasculopathy and cannot be used as a genetic risk marker. This may be because of the effects of immunosuppressive treatment.
肿瘤坏死因子-α（TNF-α）与心血管疾病有关。TNF-α基因启动子区域（-308位点）的多态性会影响个体TNF-α的产生。这会影响心脏移植后急性排斥反应的易感性。由于在心脏移植血管病变的受者中发现了最高的血清TNF-α水平，并且因为TNF-α阻断可在兔中预防该病，所以我们研究了TNF-α启动子多态性对人类心脏移植受者血管病变发展的影响。
使用针对TNF-α基因的序列特异性引物和聚合酶链反应，鉴定了147名心脏移植受者和134名心脏供者的基因型。通过常规监测冠状动脉造影诊断冠状动脉血管病变，研究高产生（A纯合子、GA杂合子）或低产生（G纯合子）TNF-α基因型与血管病变发展之间的关联。
我们发现31.9%的受者和27.0%的供者是TNF-α高产生者。TNF-α高产生等位基因的存在导致血管病变的诊断更早；高产生和低产生的心脏移植受者分别为3.42年（±91.3天）和3.84年（±76.3天）；高产生和低产生的供者移植物分别为3.52年（±87.3天）和3.78年（±77.4天）。然而，这些差异均无统计学意义。通过Kaplan Meier精算分析和对数秩检验，考虑受者（p = 0.99）或供者（p = 0.86）的TNF-α基因型时，TNF-α多态性对无血管病变情况没有影响。多变量分析确定供者年龄增加以及国际心肺移植学会3级或更高等级的急性排斥反应发作次数是受者和供者队列中血管病变的独立危险因素。
TNF-α基因启动子区域-308位点的多态性无法预测心脏移植相关血管病变的发展，不能用作遗传风险标志物。这可能是由于免疫抑制治疗的影响。
