Abstract：
BACKGROUND: T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) molecule is a key regulator of the immune response by exerting an inhibitory effect on various types of immune cells. Understanding the role of TIM-3 in hematopoietic stem cell transplantation (HSCT) may improve transplant outcomes. Our study evaluated the potential association between TIM-3 polymorphisms, namely rs1036199 (A > C) or rs10515746 (C > A), changes which are located in exon 3 and the promoter region of the TIM-3 gene, and post-HSCT outcomes.
METHODS: One-hundred and twenty allogeneic HSCT patients and their respective donors were enrolled and genotyped for TIM-3 single nucleotide polymorphisms (SNPs) using real-time PCR with TaqMan assays.
RESULTS: We found that the presence of the rare alleles and heterozygous genotypes of studied SNP in recipients tended to protect against or increase the risk for acute graft-versus-host disease (aGvHD). For the rs1036199 polymorphism, recipients with the AC heterozygous genotype (p = 0.0287) or carrying the rarer C allele (p = 0.0334) showed a lower frequency of aGvHD development along all I-IV grades. A similar association was detected for the rs10515746 polymorphism as recipients with the CA genotype (p = 0.0095) or the recessive A allele (p = 0.0117) less frequently developed aGvHD. Furthermore, the rarer A allele of rs10515746 SNP was also associated with a prolonged aGvHD-free survival (p = 0.0424). Cytomegalovirus (CMV) infection was more common in patients transplanted with TIM-3 rs10515746 mismatched donors (p = 0.0229) and this association was also found to be independent of HLA incompatibility and pre-transplant CMV-IgG status. Multivariate analyses confirmed the role of these recessive alleles and donor-recipient TIM-3 incompatibility as an independent factor in aGvHD and CMV development.
CONCLUSIONS: Polymorphism of TIM-3 molecule may affect the immune response in HSCT patients. The recessive alleles of rs1036199 and rs10515746 SNPs decreased the risk of developing aGvHD. TIM-3 donor-recipient genetic matching may also affect the risk of post-transplant CMV infection, indicating the potential value of genetic profiling in optimizing transplant strategies.
METHODS: One-hundred and twenty allogeneic HSCT patients and their respective donors were enrolled and genotyped for TIM-3 single nucleotide polymorphisms (SNPs) using real-time PCR with TaqMan assays.
RESULTS: We found that the presence of the rare alleles and heterozygous genotypes of studied SNP in recipients tended to protect against or increase the risk for acute graft-versus-host disease (aGvHD). For the rs1036199 polymorphism, recipients with the AC heterozygous genotype (p = 0.0287) or carrying the rarer C allele (p = 0.0334) showed a lower frequency of aGvHD development along all I-IV grades. A similar association was detected for the rs10515746 polymorphism as recipients with the CA genotype (p = 0.0095) or the recessive A allele (p = 0.0117) less frequently developed aGvHD. Furthermore, the rarer A allele of rs10515746 SNP was also associated with a prolonged aGvHD-free survival (p = 0.0424). Cytomegalovirus (CMV) infection was more common in patients transplanted with TIM-3 rs10515746 mismatched donors (p = 0.0229) and this association was also found to be independent of HLA incompatibility and pre-transplant CMV-IgG status. Multivariate analyses confirmed the role of these recessive alleles and donor-recipient TIM-3 incompatibility as an independent factor in aGvHD and CMV development.
CONCLUSIONS: Polymorphism of TIM-3 molecule may affect the immune response in HSCT patients. The recessive alleles of rs1036199 and rs10515746 SNPs decreased the risk of developing aGvHD. TIM-3 donor-recipient genetic matching may also affect the risk of post-transplant CMV infection, indicating the potential value of genetic profiling in optimizing transplant strategies.
摘要：
背景：T细胞免疫球蛋白和含粘蛋白结构域3（TIM-3）分子通过对各种类型的免疫细胞发挥抑制作用，是免疫应答的关键调节剂。了解TIM-3在造血干细胞移植（HSCT）中的作用可能会改善移植结果。我们的研究评估了TIM-3多态性之间的潜在关联，即rs1036199（A>C）或rs10515746（C>A），位于外显子3和TIM-3基因启动子区的变化，和HSCT后结果。
方法：招募了120名同种异体HSCT患者及其各自的供体，并使用实时PCR和TaqMan分析对TIM-3单核苷酸多态性（SNP）进行基因分型。
结果：我们发现受体中所研究的SNP的罕见等位基因和杂合基因型的存在倾向于预防或增加急性移植物抗宿主病（aGvHD）的风险。对于rs1036199多态性，具有AC杂合基因型(p=0.0287)或携带较罕见的C等位基因(p=0.0334)的受者在所有I-IV等级中显示出较低的aGvHD发展频率.rs10515746多态性检测到类似的关联，因为具有CA基因型（p=0.0095）或隐性A等位基因（p=0.0117）的接受者较少发生aGvHD。此外，rs10515746SNP的罕见A等位基因也与延长的无aGvHD生存期相关(p=0.0424).巨细胞病毒（CMV）感染在移植了TIM-3rs10515746错配供体的患者中更为常见（p=0.0229），并且还发现这种关联与HLA不相容性和移植前CMV-IgG状态无关。多变量分析证实了这些隐性等位基因和TIM-3不相容性在aGvHD和CMV发展中的作用。
结论：TIM-3分子多态性可能影响HSCT患者的免疫反应。rs1036199和rs10515746SNP的隐性等位基因降低了发生aGvHD的风险。TIM-3供体-受体遗传匹配也可能影响移植后CMV感染的风险，表明遗传分析在优化移植策略中的潜在价值。
方法：招募了120名同种异体HSCT患者及其各自的供体，并使用实时PCR和TaqMan分析对TIM-3单核苷酸多态性（SNP）进行基因分型。
结果：我们发现受体中所研究的SNP的罕见等位基因和杂合基因型的存在倾向于预防或增加急性移植物抗宿主病（aGvHD）的风险。对于rs1036199多态性，具有AC杂合基因型(p=0.0287)或携带较罕见的C等位基因(p=0.0334)的受者在所有I-IV等级中显示出较低的aGvHD发展频率.rs10515746多态性检测到类似的关联，因为具有CA基因型（p=0.0095）或隐性A等位基因（p=0.0117）的接受者较少发生aGvHD。此外，rs10515746SNP的罕见A等位基因也与延长的无aGvHD生存期相关(p=0.0424).巨细胞病毒（CMV）感染在移植了TIM-3rs10515746错配供体的患者中更为常见（p=0.0229），并且还发现这种关联与HLA不相容性和移植前CMV-IgG状态无关。多变量分析证实了这些隐性等位基因和TIM-3不相容性在aGvHD和CMV发展中的作用。
结论：TIM-3分子多态性可能影响HSCT患者的免疫反应。rs1036199和rs10515746SNP的隐性等位基因降低了发生aGvHD的风险。TIM-3供体-受体遗传匹配也可能影响移植后CMV感染的风险，表明遗传分析在优化移植策略中的潜在价值。
