Interleukin-10 and tumor necrosis factor alpha region haplotypes predict transplant-related mortality after unrelated donor stem cell transplantation

Abstract

Certain cytokine gene polymorphisms have been shown to correlate with outcome of human leukocyte antigen (HLA) identical sibling donor stem cell transplantation (SCT), but in unrelated donor SCT such information is scarce. We have studied the association between cytokine gene polymorphism and transplant-related mortality (TRM) in 182 unrelated SCTs performed at a single center. We found association of polymorphism in the tumor necrosis factor alpha (TNF␣) and interleukin-10 (IL-10) gene and TRM. Both the TNFd4 allele and the TNF␣ ؊1031C alleles are associated with high risk for TRM. Statistical analysis showed that both polymorphisms were present on a single haplotype. This haplotype was associated with high risk of TRM when present in recipient or donor, 55% (43%-67%) compared with 21% (12%-30%) when absent from both (P < .01). A further allele associated with this haplotype, TNFa5, is also associated with increased risk of TRM.

Cytokine gene polymorphisms and graft-versus-host disease in children after matched sibling hematopoietic stem cell transplantation: a single-center experience

“…7 In a large cohort of HLA-matched sibling transplants, the presence of the IL-10 ATA/ACC genotype in the recipient has been associated with a moderate risk of GVHD and lower risk of death in remission, 16 more severe GVHD occurring in groups without the IL-10 ATA haplotype. The study by Lin et al 16 assessed overall survival, allele frequency and genotypes at each IL-10 SNP and showed that the risk of death was the lowest in recipients who were homozygous for the -592A allele.…”

“…In another study of unrelated donor transplants, TRM was associated with the higher IL-10 producer GCC haplotype when present in the donor. 7 However, the lower producer allele (IL-10-1082A) has also been associated with poor survival. 22 Furthermore, it was shown that patients with ATA haplotypes required more prolonged immunosuppression due to increased incidence of cGVHD and were more susceptible to pulmonary aspergillosis, whereas the ACC haplotype reduced the risk of pulmonary aspergillosis ninefold.…”

“…5 In the last decade several groups showed the predictive value of certain polymorphisms at genes encoding for pro-and anti-inflammatory cytokines for transplant outcome following both matched related and unrelated HSCT. [6][7][8] However, published data have been inconsistent, probably reflecting the heterogeneity of the transplant cohorts regarding age of recipient, disease status, type of donor, source of stem cells, etc. In addition, most of the published studies have been undertaken in adult recipient-donor pairs and very few in children.…”

Protective role of interleukin-10 promoter gene polymorphism in the pathogenesis of invasive pulmonary aspergillosis after allogeneic stem cell transplantation

“…9 Recently, the IL-10 promoter gene SNP was found to be associated with acute 10 or chronic GVHD, 11,12 or transplant-related mortality (TRM) in an allogeneic transplant setting. 13 Moreover, the role of IL-10 in the local host defense mechanism in the lungs may also affect the pathogenesis of IPA. 14 However, data on the association of the IL-10 promoter gene SNP with the pathogenesis of IPA after allogeneic SCT is scarce.…”

The impact of frequent HLA haplotypes in high linkage disequilibrium on donor search and clinical outcome after unrelated haematopoietic SCT

“…5 The role of some of these non-HLA genes have been studied (reviewed [6][7][8][9][10] ): single nucleotide polymorphisms and/or microsatellites within cytokine (-receptor) genes and other non-HLA encoded genes, including those of the innate immune system, may indeed influence HSCT outcome. [11][12][13][14][15][16][17] Genes in the TNF block, MICA/MICB and microsatellite markers are of specific interest because they are in linkage disequilibrium (LD) with the classical HLA genes and could be inherited together as one genetic unit. [13][14][15][18][19][20][21] The presence of FH in patients also affects the probability and speed of identifying a matched UD.…”