Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
Biol Blood Marrow Transplant. 2010 Jul;16(7):927-936.e1. doi: 10.1016/j.bbmt.2010.01.009. Epub 2010 Jan 25.
Tumor necrosis factor (TNF)-alpha plays a significant role in conditioning related toxicities and the development of acute graft-versus-host disease (aGVHD). TNF-alpha gene polymorphisms are associated with rejection after organ transplantation and aGVHD in matched related donor blood and marrow transplantation (BMT) recipients. Few studies have been published on unrelated donor BMT in the pediatric age group. In this study, we examined the relationship between specific polymorphisms in TNF pathway genes and the occurrence and severity of aGVHD. Recipient single-nucleotide polymorphisms (SNPs) in TNF-alpha and TNF receptor superfamily members 1A (TNFRSF1A) and 1B (TNFRSF1B) were investigated. In a multi-institutional Pediatric Blood and Marrow Transplant Consortium trial, a total of 180 pediatric patients (mean age, 11.0 years) were prospectively evaluated for clinical outcomes after matched unrelated donor BMT. All patients received myeloablative conditioning and two-drug GVHD prophylaxis with cyclosporine or tacrolimus, with methotrexate in the majority of patients. TNF-alpha genotypes were not correlated with the overall incidence of aGVHD. Significant associations were seen between TNF-alpha variant alleles and the severity of aGVHD (grade II-IV and grade III-IV), especially when analyzed in whites only (n = 165). Grade II-IV aGVHD was correlated with recipient -857T allele (hazard ratio [HR], 0.47; P = .04), -238A allele (HR, 1.76; P = .002), and d3/d3 genotype (HR, 0.64; P = .03). Severe (grade III-IV) aGVHD was associated with TNF-alpha -1031C allele (HR, 2.38; P = .03), -863A allele (HR, 3.18; P = .003), and d4/d4 genotype (HR, 2.82; P = .01). After adjusting for clinical factors, the association of -1031C, -863A, -238A, and d4/d4 genotypes with severity of aGVHD remained statistically significant. No correlation between selected SNPs in TNFRSF1A or TNFRSF1B and the incidence or severity of aGVHD was found. Our findings indicate clinically important relationships between genetic polymorphisms in TNF-alpha and the severity of aGVHD in this cohort. Improved understanding of this relationship may allow for a risk-adjusted approach to GVHD prevention in pediatric BMT.
肿瘤坏死因子（TNF）-α 在调节相关毒性和急性移植物抗宿主病（aGVHD）的发展中起重要作用。TNF-α 基因多态性与器官移植后排斥反应以及匹配相关供体血液和骨髓移植（BMT）受者的 aGVHD 有关。关于儿科年龄组无关供体 BMT 的研究较少。在这项研究中，我们研究了 TNF 通路基因的特定多态性与 aGVHD 的发生和严重程度之间的关系。研究了受体 TNF-α 和 TNF 受体超家族成员 1A（TNFRSF1A）和 1B（TNFRSF1B）中的单核苷酸多态性（SNP）。在多机构儿科血液和骨髓移植协会试验中，前瞻性评估了 180 例接受匹配无关供体 BMT 的儿科患者的临床结局。所有患者均接受了清髓性预处理和环孢素或他克莫司的二药 GVHD 预防，大多数患者使用甲氨蝶呤。TNF-α 基因型与 aGVHD 的总发生率无相关性。仅在白人中进行分析时，TNF-α 变体等位基因与 aGVHD 的严重程度（Ⅱ-Ⅳ级和Ⅲ-Ⅳ级）之间存在显著关联（n=165）。Ⅱ-Ⅳ级 aGVHD 与受体 -857T 等位基因（风险比[HR]，0.47；P=0.04）、-238A 等位基因（HR，1.76；P=0.002）和 d3/d3 基因型（HR，0.64；P=0.03）相关。严重（Ⅲ-Ⅳ级）aGVHD 与 TNF-α-1031C 等位基因（HR，2.38；P=0.03）、-863A 等位基因（HR，3.18；P=0.003）和 d4/d4 基因型（HR，2.82；P=0.01）相关。在调整临床因素后，-1031C、-863A、-238A 和 d4/d4 基因型与 aGVHD 严重程度的相关性仍具有统计学意义。TNFRSF1A 或 TNFRSF1B 中选定 SNP 与 aGVHD 的发生率或严重程度之间无相关性。我们的研究结果表明，TNF-α 基因多态性与该队列中 aGVHD 的严重程度之间存在重要的临床相关性。对这种关系的深入了解可能允许在儿科 BMT 中对 GVHD 进行风险调整预防。
