Genetic variation of TNF-α and IL-10, IL-12, IL-17 genes and association with torque teno virus infection post hematopoietic stem cell transplantation

Abstract

Little is known about the role of genetic variation in the genes for cytokines and susceptibility to viral infection especially torque teno virus (TTV) following allogeneic hematopoietic stem cell transplantation. In this study, the association between interleukin-12, interleukin-17, interleukin-10 (IL-12,-17,-10) and tumor necrosis factor α (TNF-α) polymorphisms was evaluated in patients with TTV infection who underwent allogeneic hematopoietic stem cell transplantation from South of Iran. The single nucleotide polymorphisms in the cytokine genes including IL-12 (-1188A/C), IL-17 (-197G/A), IL-10 (-1082G/A,-819C/T and-592C/A) and TNF-α (-308 G/A) were analyzed by PCR-RFLP methods. While our results did not show any association between IL-17, IL-12 and IL-10 (-819C/T and-1082G/A) polymorphisms and TTV infection status, heterozygote genotype of IL-10 (-592C/A) had direct correlation with TTV infection and A allele of TNF-α (-308G/A) showed a protective effect against TTV infection (P = 0.05 and P = 0.025, respectively). Within the group of patients who experienced acute graft-versus-host disease, the AA genotype and the A allele of IL-17 (-197 G/A) were significantly higher in non-infected patients compared to infected ones (p = 0.024 and p = 0.057, respectively). It was also observed that among infected patients, the GG genotype of IL-17 and AA genotype of TNF-α were significantly increased in hematopoietic stem cell transplanted patients with low grade (grade I+II) acute graftversus-host disease compared to high grade (grade III and IV) disease (p = 0.056 and p = 0.056, respectively). Taken together, genetic variation of IL-10 (-592C/A) and TNF-α (-308G/A) genes might be associated with susceptibility to TTV infection post hematopoietic stem cell transplantation.

Impact of polymorphisms in genes orchestrating innate immune responses on replication kinetics of Torque teno virus after kidney transplantation

“…The present investigation is the first to evaluate to what extent the kinetics of TTV DNA levels following KT are influenced by SNPs in genes coding for PRRs (TLR3, TLR9 and CD209), ILs and cytokines (IL-12B, IL-17, IL-10, TNF), IFN-λ3 (IL-28B) and the costimulatory receptor CTLA-4). These candidate SNPs were chosen on the basis of prior studies performed in the HSCT population (Ramzi et al, 2019;Ramzi et al, 2021) or due to their well-established involvement in other viral infections in SOT recipients (Redondo et al, 2022d). We found no clear association between any of the SNP genotypes considered and various parameters reflecting viral kinetics after transplantation, such as mean and peak DNA levels or AUCs for plasma TTV DNAemia during discrete periods, or absolute increments from baseline.…”

“…Nevertheless, the relative contribution of the innate system—and its genetic determinants—has not been characterized so far. To our knowledge only three previous works have analyzed the impact of genetic polymorphisms on TTV replication in HSCT recipients (with two studies from the same group) and people living with human immunodeficiency virus (HIV) ( Prasetyo et al, 2015 ; Ramzi et al, 2019 ; Ramzi et al, 2021 ). Ramzi et al (2019) ; Ramzi et al (2021) found a correlation between SNPs in IL10 , CTLA4 and TNF genes and TTV infection in allogeneic HSCT recipients.…”

“…To our knowledge only three previous works have analyzed the impact of genetic polymorphisms on TTV replication in HSCT recipients (with two studies from the same group) and people living with human immunodeficiency virus (HIV) ( Prasetyo et al, 2015 ; Ramzi et al, 2019 ; Ramzi et al, 2021 ). Ramzi et al (2019) ; Ramzi et al (2021) found a correlation between SNPs in IL10 , CTLA4 and TNF genes and TTV infection in allogeneic HSCT recipients. In detail, the heterozygote genotypes of IL10 rs1800872 (−592C/A) and CTLA4 rs231775 (+49 A/G) were associated with a higher prevalence of TTV DNAemia, whereas the A allele of TNF rs1800629 (−308G/A) had a protective effect.…”

“…We analyzed the SNPs located in IFNL4 (rs12979860, rs8099917) due to its well-established relevance in other viral infections, including CMV ( Fernandez-Ruiz et al, 2015 ) and hepatitis C virus (HCV) ( Ge et al, 2009 ; Thomas et al, 2009 ). Finally, we aimed to validate in the SOT population the associations reported by other authors between CTLA4 (rs5742909, rs231775), TNF (rs1800629), IL10 (rs1800872, rs1878672), IL12B (rs3212227) and IL17 (rs2275913) SNPs and the kinetics of TTV DNAemia after HSCT ( Ramzi et al, 2019 ; Ramzi et al, 2021 ).…”

“…Indeed, various studies have shown a direct correlation between TTV DNA loads and calcineurin inhibitors trough levels ( Gorzer et al, 2014 ; Jaksch et al, 2018 ). The role played by the innate immune arm in the setting of ongoing immunosuppression remains largely unknown, as is the potential impact of polymorphisms in genes coding for PRRs (such as toll-like receptors [TLRs]), interleukins (IL) or interferons (IFNs) ( Prasetyo et al, 2015 ; Ramzi et al, 2019 ; Ramzi et al, 2021 ). Evidence of an individual genetic susceptibility to TTV regardless of the amount of immunosuppressive therapy would question the reliability of viral replication as clinical biomarker in the SOT population.…”