Bettens Florence, Passweg Jakob, Gratwohl Alois, Chalandon Yves, Helg Claudine, Chapuis Bernard, Schanz Urs, Libura Jolanta, Roosnek Eddy, Tiercy Jean-Marie
Transplantation Immunology Unit/LNRH, University Hospital, Geneva, Switzerland.
Transplantation. 2006 May 15;81(9):1261-7. doi: 10.1097/01.tp.0000208591.70229.53.
Non-HLA immunogenetic polymorphisms may influence outcome of hematopoietic stem cell transplantation (HSCT). In this study, we have determined the role of TNFa, TNFd, IL-10, IL-1, IL-1Ra, and IL-4R polymorphisms in patients transplanted with HSC of an unrelated donor.
The allelic variants of four SNPs (IL-10-1082, IL-1beta-511, IL-4R-3223, IL-4R-1902) and four microsatellites (TNFa, TNFd, IL-10-1064, IL-1Ra) were determined in 131 unrelated patient/donor pairs typed for HLA-A/B/C/DR/DQ (four digits).
The allelic distribution of the polymorphisms was similar to that previously reported in Caucasoid populations. Patient and donor TNFd and patient IL-10-1064 polymorphisms correlated with mortality in univariate analysis. Patients with TNFd1/d2/d3 genotypes had 3-year survival rates of 65%. A gradual decrease in survival rates was observed for patients with TNFd3/d3 genotypes (50%, p=n.s.), TNFd4 (46%, P=0.08), and TNFd5 (33%, P=0.03). A multivariate analysis of 10/10 matched patients revealed that the following patient genotypes correlated with lower survival: TNFd3/d3 (RR 4.08, P=0.026) TNFd4 (RR 3.78, P=0.032) and TNFd5 (RR 6.69, P=0.021) all compared to TNFd1/d2/d3 genotypes. Patient IL-10 (12, 14, 15) microsatellite alleles correlated with lower 3-year survival (28%) when compared to IL-10 (<12) (56%, P=0.052) and to Il-10 (13) alleles (60%, P=0.0023). In multivariate analysis this correlation remained significant only in recipients of HSCT of 10/10 HLA matched donors (RR=2.96, P=0.038).
The data demonstrate a significant correlation of the TNFd and IL-10-1064 microsatellite polymorphisms with mortality after unrelated HSCT. They support the hypothesis that simple genomic tests, in addition to precise HLA matching, may contribute to determine prognosis in patients undergoing unrelated HSCT.
非人类白细胞抗原（HLA）免疫遗传多态性可能影响造血干细胞移植（HSCT）的结果。在本研究中，我们确定了肿瘤坏死因子α（TNFα）、肿瘤坏死因子δ（TNFδ）、白细胞介素10（IL-10）、白细胞介素1（IL-1）、白细胞介素1受体拮抗剂（IL-1Ra）和白细胞介素4受体（IL-4R）多态性在接受无关供体造血干细胞移植患者中的作用。
在131对经HLA-A/B/C/DR/DQ（四位数字）分型的无关患者/供体对中，确定了四个单核苷酸多态性（IL-10 -1082、IL-1β -511、IL-4R -3223、IL-4R -1902）和四个微卫星（TNFα、TNFδ、IL-10 -1064、IL-1Ra）的等位基因变异。
多态性的等位基因分布与先前在白种人群中报道的相似。在单变量分析中，患者和供体的TNFδ以及患者的IL-10 -1064多态性与死亡率相关。TNFδ1/d2/d3基因型的患者3年生存率为65%。TNFδ3/d3基因型（50%，P=无统计学意义）、TNFδ4（46%，P=0.08）和TNFδ5（33%，P=0.03）的患者生存率逐渐下降。对10/10匹配患者的多变量分析显示，与TNFδ1/d2/d3基因型相比，以下患者基因型与较低生存率相关：TNFδ3/d3（相对风险度4.08，P=0.026）、TNFδ4（相对风险度3.78，P=0.032）和TNFδ5（相对风险度6.69，P=0.021）。与IL-10（<12）（56%，P=0.052）和IL-10（13）等位基因（60%，P=0.0023）相比，患者IL-10（12、14、15）微卫星等位基因与较低的3年生存率（28%）相关。在多变量分析中，这种相关性仅在10/10 HLA匹配供体的HSCT受者中仍然显著（相对风险度=2.96，P=0.038）。
数据表明TNFδ和IL-10 -1064微卫星多态性与无关供体HSCT后的死亡率显著相关。它们支持这样的假设，即除了精确的HLA匹配外，简单的基因组检测可能有助于确定接受无关供体HSCT患者的预后。
