A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation

Abstract

Interleukin (IL)-6 is an important regulator of immunity and inflammation in many diseases. Single nucleotide polymorphisms (SNPs) in the IL-6 gene influence outcome after allogeneic stem cell transplantation (ASCT), but the possible importance of SNPs in the IL-6 receptor has not been examined. We therefore investigated whether SNPs in the IL-6R gene influenced biochemical characteristics and clinical outcomes after ASCT. We examined the IL-6 promoter variant rs1800975 and the IL-6R SNPs rs4453032, rs2228145, rs4129267, rs4845374, rs4329505, rs4845617, rs12083537, rs4845618, rs6698040 and rs4379670 in a 101 population-based cohort of allotransplant recipients and their family donors. Patients being homozygous for the major alleles of the IL-6R SNPs rs2228145 and rs4845618 showed high pretransplant CRP serum levels together with decreased sIL-6R levels; the decreased IL-6R levels persisted 6 months post-transplant. In contrast, patients being homozygous for the minor allele of the IL-6R SNP rs4379670 showed decreased pretransplant CRP levels. Furthermore, the IL-6R rs4845618 donor genotype showed an association with severe acute graft-versus-host disease (GVHD), whereas the donor genotype of the IL-6 SNP rs1800795 was associated with decreased survival 100 days post-transplant. Finally, the recipient genotype of the IL-6R SNP rs4329505 showed a strong association with 2-years non-relapse mortality, and this effect was also highly significant in multivariate analysis. IL-6 and IL-6R SNPs influence the clinical outcome after allogeneic stem cell transplantation.

Association of recipient and donor interleukin 6 polymorphisms 174 and 597 with outcome after allogeneic hematopoietic stem cell transplantation in children

“…We observed that patients with the IL6-174 GG genotype developed acute GVHD (grade II–IV) more frequently than individuals with the C allele. While our data are in agreement with most previous studies which suggest a relationship between the IL6-174 GG genotype of the recipients and an increased risk for development of acute GVHD (Ambruzova et al 2009 ; Cavet et al 2001 ; Dickinson and Charron 2005 ; Dukat-Mazurek et al 2017 ), other authors did not observe an association between IL6-174 SNP and acute GVHD (Lin et al 2003 ; Mullighan et al 2004 ; Tvedt et al 2018 ). To our knowledge, only one study focused on a detailed analysis of the impact of IL6-597 SNP on the outcome of allogeneic HSCT.…”

“…We did not find any significant relationships between OS, EFS, RI, TRM and the IL6-174 and IL6-597 polymorphisms of recipient and donor. Ambruzova et al (2009) and Tvedt et al (2018) described an association between the IL6-174 polymorphism and TRM. Ambruzova et al (2009) and Balavarca et al (2015) observed a relationship between OS and IL6-174 G allele.…”

Interleukin-6 as Biomarker for Acute GvHD and Survival After Allogeneic Transplant With Post-transplant Cyclophosphamide

“…The candidate biomarker of our study was IL6, a cytokine associated with several inflammatory diseases, and a modulator of the immune responses involved in aGvHD pathogenesis (12, 34–36). IL6 can be targeted with a selected inhibitory strategy based on anti-IL6 receptor antibody (10), tocilizumab (TCZ).…”

Immunological heterogeneity of healthy peripheral blood stem cell donors – preharvesting donor characteristics, additional heterogeneity induced by granulocyte colony-stimulating factor and possible importance for outcome after allotransplantation

“…Single-nucleotide polymorphisms (SNPs) of cytokine or cytokine receptor genes that seem to influence posttransplant outcome include IL-10 promoter gene polymorphisms, TNFd4, TNFα-1031C, IL-6 promoter variants, IL-6 receptor SNPs, CCL5-28CG, CCR9-926AG, IL-23 receptor 1142 GA, and IL-7 receptor α 1237AG [5,6]. They influence both acute and chronic GVHD (severity and organ involvement) as well as susceptibility to infections.…”