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Association Between Polymorphisms in Cytokine Gene and Viral Infections in Renal and Liver Transplant Recipients: A Systematic Review.

PURPOSE
Although transplantations are associated with an increased risk of post-transplantation infections, they greatly improve life expectancy and patients' quality of life. Cytokine genes play an important role in the success of transplants due to their immunological functions. A systematic review was conducted to evaluate cytokine gene polymorphisms and risk of cytomegalovirus (CMV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in kidney and liver transplant recipients.


METHODS
A systematic search was conducted using PubMed, EMBASE, Medline and Google Scholar from their inception until January 28, 2019 using appropriate key words. Review articles, case reports or series, studies conducted on non-human subjects and published in languages other than English were excluded. Data were abstracted using a standardized form. The quality of the studies included was assessed using "Risk of Bias Assessment tool for Non-randomized Studies (RoBANS)".


RESULTS
Thirty-one studies met our inclusion criteria; populations studied were diverse with a sample ranging from 20 to 1,671. Nineteen studies evaluated Interleukin (IL)-28B polymorphism, while six studies evaluated interferon lambda (IFN-λ) gene polymorphisms and their impact on CMV, HCV, and HBV progression. Polymorphisms in IL-10 gene were investigated in six studies. Polymorphisms in IL-12B and IL-1B gene were associated with a higher risk of developing CMV infections while polymorphisms in IL-28B were associated with a lower incidence of CMV infection in renal transplant recipients. Similarly, polymorphisms in IL-28B were associated with higher liver dysfunction from HBV infection in liver transplant recipients. Studies included had low risk of bias.


CONCLUSIONS
Cytokine gene polymorphisms IL-12B and IL-1B were found to be associated with an increased risk of infection in kidney transplants and IL-28B in liver transplant recipients. However, the small number and heterogeneity of studies limits the generalization of our results. Further research may lead to finding these associations in larger studies which perhaps improve the use of genetic testing and targeted antiviral therapy. This will further reduce the risk of viral infections associated with cytokine gene polymorphisms in post renal and liver transplant recipients.


INTRODUCTION
Solid organ transplants remain the last possible recourse for some patients with organ failure. Transplants represent improvement in the quality of life for dialysis patients and those with other chronic disease states by offering them a second opportunity at life. Over 135,000 solid organ transplants were performed worldwide in 2016; over 34,000 of these were performed in the United States and there are more than 114,000 people are on the waiting list as of April 2018 (1, 2). The most common solid organ transplants are renal transplants followed by liver transplants. Unfortunately, transplants pose a high risk for infections which can be a major cause of morbidity and mortality among patients after transplantation. In fact, it is the second leading cause of death in patients with renal transplants (3). Those who undergo transplantation are highly susceptible to both bacterial and viral infections due to the immunosuppressive therapy which is used to prevent transplant rejection. Post-transplantation infections include those caused by Streptococcus pneumoniae, cytomegalovirus (CMV), Hepatitis C virus (HCV) _ and BK polyomavirus. Renal and hepatic transplant graft survival is severely complicated by these infectious pathogens.
CMV infection is the most common opportunistic infection and is a major cause of posttransplant infection (4). CMV is a double stranded deoxyribonucleic acid (DNA) virus and mostly presents as a latent virus that can be reactivated posttransplantation. CMV occurs in 8-32% of renal transplant recipients. CMV disease was associated with an increased risk of graft rejection or loss (5). There are several risk factors that contribute to the development of CMV infection such as age, concomitant infections, immunosuppression, and genetic polymorphisms (4). The infection typically does not cause symptoms in its latent phase but may present flu-like symptoms in the host when reactivated and can affect many organs. Elevated liver enzymes, thrombocytopenia and leukopenia can occur in the host (4).
Similar to renal transplants, liver transplants are also susceptible to viral infection and subsequent allograft rejection. Viral hepatitis is characterized by inflammation of the liver, and its pathogenesis, disease progression, and treatment are influenced by cytokines. In the three major stages of hepatitis infection -namely acute, chronic, and cirrhosiscytokines play a prominent role in the first two stages when the disease is in the development and maintenance stage (6). Among the five types of hepatitis virus (A, B, C, D, E), the main focus of cytokines is on HCV and HBV pathogenesis, graft survival or rejection, and treatment outcome. In patients who receive liver transplants with HCV recurrence, 10-20% of them develop cirrhosis within five years, compared to the general population who develop cirrhosis within twenty to thirty years (7). HBV can also cause liver cirrhosis and is a major public health concern due to risk of death. According to the World Health Organization, around 650,000 people will pass away due to complications associated with HBV (7).
Cytokines are a large class of proteins and are essential elements in both the adaptive and innate immune system and can affect cells in the body which mobilize and induce inflammation during infection (7). Interestingly, cytokines can have dual roles in the development and progression of viral infection in liver and kidney transplant patients. Certain proteins demonstrate anti-viral properties compared to others which facilitate immunemediated inflammatory effects. Similar to most viral infections, subsequent to HCV and HBV infections, the body attempts to clear the viral load through an immune response via cytokines such as interleukin (IL), tumor necrosis factor-alpha (TNF-α) and interferon (IFN) (8). In the absence of appropriate cytokine functions, the HCV or HBV infections eventually lead to fibrogenesis of the liver and require a liver transplant. The success of a liver transplant is considerably dependent on the status of cytokine functions (8). Cytokines play an important role in CMV, HBV, and HCV infections, as well as triggering the induction of these cytokines during infection (9). There is evidence that cytokines have a protective role in CMV infections, as they produce IFN-λ and IL, but cytokines also induce T-cells that cause chronic inflammation-related tissue damage if unregulated (9).
Different forms of cytokine genes arising from the variation in the DNA sequence or polymorphism can lead to altered functionality of cytokines, which in turn can differentially affect the development, progression, and treatment of viral infections (10). Single-nucleotide polymorphisms (SNP) in cytokines, which occur from changes in a single nucleotide base leading to altered protein and function, may be associated with a susceptibility to and an increased risk of infection and response to antiviral treatments (10). The role of cytokine gene polymorphisms and their associations with CMV infection have yet to be fully studied. The presence of these SNPs may predict a patient's outcome during post-transplantation. Further research is needed and exploration into these polymorphisms is essential in order to improve health outcomes in patients with solid organ transplants, such as renal and liver transplants, and other disease conditions. This is crucial in order to guide therapy and tailor drugs to a patient's genetic makeup in order to prevent complications from infections and to ensure graft and patient survival.
Several studies have broadly investigated the association of cytokine gene polymorphisms and different types of infections post solid organ transplant. However, there are limited studies that have systematically assessed the impact of cytokine polymorphisms on CMV infection in renal transplant recipients and HBV and HCV infection among liver transplant recipients. The aim of this study is to explore whether in renal and liver transplant recipients (population), are cytokine gene polymorphisms (Exposure/Non-exposure) associated with risk of CMV, HBV and HCV infections (Outcomes) by using the Patient or Population, Intervention or Exposure, Comparison and Outcomes (PICO) framework. This review primarily focuses on systematically organizing and analyzing the association between cytokine gene polymorphism and CMV in renal transplant recipients and HBV and HCV in liver transplant recipients.

Data sources, search terms and inclusion criteria:
A search was performed through Medline (up to January 2019), EMBASE (up to January, 2019), PubMed (up to January, 2019) and Google Scholar (up to January, 2019) to identify studies that examined the associations between cytokine gene polymorphisms and CMV in renal transplant and HBV and HCV in liver transplant recipients. The following keywords were used in the search -''cytokine", "cytokine gene", ''polymorphism", "polymorphism, genetic", ''Cytomegalovirus", "Hepatitis B", "Hepatitis C", "Hepatitis", "viral infections", "renal transplantation", "kidney transplantation", "renal transplant", "liver transplantation", "liver transplant", "solid organ transplantation", "solid organ transplant" (Appendix S1). The last search was performed on January 28, 2019. At first, titles and abstracts were screened for their inclusion, followed by a screening of the full texts. Review articles, case reports or studies, studies conducted in other than human subjects, performed in other than renal and liver transplant recipients, and articles published in other than the English language were excluded.

Data extraction
Electronic database searches were performed by all authors. The two investigators (SB and PS) assessed the eligibility and quality of all studies included according to the predetermined selection criteria. Information was extracted independently by all authors from eligible publications using a data abstraction form which included the following: Authors, year of publication, country of origin, study design, sample size, genotype, polymorphisms and its impact on transplant outcome (post-transplant infection) (Appendix S2). Discrepancies between the investigators were discussed and resolved by consensus.

Quality of publications
The quality of publications was assessed using Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). The RoBANS tool contains six domains, including the selection of participants, confounding variables, measurement of the intervention (exposure), blinding of the outcome assessment, incomplete outcome data, and selective outcome reporting (11). RoBANS is a validated tool that is reliable and feasible for the assessment of the methodological quality of non-randomized studies. Review Manager version 5.3.3 was used to generate a summary of the RoBANS results (12). Our review was designed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist (13) (Appendix S3).

Study characteristics:
Our screening identified 73 potentially relevant articles. A total of 31 studies were included that met our inclusion criteria (Figure 1).
Nine studies explored the association of cytokine gene polymorphism and post-transplant CMV infection in renal transplant recipients, six studies assessed the association with HBV and 16 studies looked at its association with HCV infection post liver transplantation. Fourteen studies were from a European population, six studies were from Asian populations, and 11 studies were performed in a mixed population. Nineteen studies were performed to evaluate IL-28B polymorphism in renal and hepatic transplant patients, while 6 studies evaluated the association between IFN-λ gene polymorphism and its impact on the progression of CMV, HCV, and HBV. Polymorphisms in IL-10 were investigated in six studies. The characteristics of the studies included are presented in Table 1. The quality assessment of included non-randomized studies based on RoBANS tool is presented in Table 2.   The studies included showed low risk of bias for both blinding for outcome assessment and selective outcome reporting domain of the tool in all of the studies, high risk of bias for selection of the participants and confounding variables domain in five studies and unsure risk of bias for intervention measurement and incomplete outcome data domain in two studies ( Figure 2).

Role of Cytokines in Renal Transplant
A lower incidence of CMV infection was found in patients with A-allele genotypes of toll like receptor 2 (TLR-2) and T-allele genotypes of IL-28B. Patients with the A-allele were less susceptible to CMV infection compared to patients with the GG genotype (14). The 12-month CMV infection free survival rate was 85%, compared to 53% in patients with the GG genotype. The survival rate was also higher among patients with the TT genotype of TLR-9 compared to those with the AA/AG genotypes of dendritic cell-specific ICAM 3-grabbing nonintegrin (DC-SIGN) SNP, 54% compared to 40%, respectively. This effect was found to be more pronounced in patients not on prophylaxis therapy and was also associated with a lower risk of CMV infection. This study concluded a significant relationship between the number of unfavorable SNP genotypes and the overall risk of CMV infection, specifically, SNPs in IL-28B, TLR-9, and DC-SIGN genes may have modulated the susceptibility to CMV infection in these patients (14). In another study, the incidence of CMV replication emerged to be higher among recipients who were homozygous for the minor allele of rs368234815 (-G/-G carriers) compared with other patients (TT/TT or TT/-G carriers). The results of this study indicated that IFN-λ rs368234815 polymorphism might be a risk factor for developing CMV associated complications post-renal transplantation (15). In a retrospective study conducted in Spain, 205 patients developed CMV infection and the median time to onset was 2.7 months (15). However, Santiago and colleagues found no association of IFN-λ-874 A/T polymorphism as a predictive marker of CMV infection in their analyses (16). Previously, the Callele was found to be an independent risk factor for CMV infection on a multifactorial Cox regression analysis. This risk was estimated to be even higher in patients with a positive CMV serological status before the transplantation and who did not receive prophylaxis (17). Programmed cell death protein (PD)-1 is known to inhibit IFN-λ production and has been reported to be clinically relevant in immune disorders. Forty six percent of those that were carriers of the A-allele acquired CMV infection. It has been hypothesized that the A-allele could affect PD-1 inhibition and increase inflammatory mediators post kidney transplantation (18). Hoffman and colleagues in this study further concluded that the A-allele was associated with risk of CMV infection in those who did not receive prophylaxis. In patients with PD-1.3, the A-allele had a much higher risk of CMV infection and prophylaxis based on genetic markers, which needs to be further researched (18).
Cytokine polymorphisms (IL-10, transforming growth factor beta (TGF-B), TNF-α, IFN-λ, IL-6, IL-4, IL-2, IL-4R, IL-12, IL-4RA, IL-1RA, IL-1R, IL-1B, and IL-1A) were studied to determine the relationship between cytokine polymorphisms and infection in kidney transplant recipients (19). A total of 122 patients developed at least one instance of infection within the first year. Female patients developed infections more than their male counterparts. Recipients with -511 IL-1B CC genotype or with -1188 IL-12 CA and CC genotypes were at higher risk of developing infections in the first year. These genotypes predicted the risk of posttransplantation infection in the first year after transplantation (19).
Seventy-one CMV seronegative recipients of grafts from CMV seropositive donors were studied in Finland where IL-10, IL-6, and IFN-λ gene polymorphisms were explored for the links between these genes and infection. The donor IL-10 (-1082 AA) genotype reduced the incidence of CMV infection, suggesting that gene polymorphism may impact the likelihood of CMV infection in high risk patients (20). A lower risk of CMV reactivation in those with AA genotypes compared to AT genotypes of the IFN-λ gene was predicted in a large sample in this Spanish study. No genotypes conferred a protective effect among polymorphisms in IL-28B. The authors found no differences between IFN-λ levels in those with and without CMV replication and no differences between peak viral load, duration, or onset of replication due to a small sample size (21).
Patients with donor-positive/recipient-negative (D+/R-) serostatus were found to be associated with a high risk of CMV infection among Hispanic renal transplant recipients in this study by Vu et al (22). A significant association was found between IFN-γ +874 A>T polymorphism and the risk of CMV infection. The IFN-γ +874 AA genotype was associated with a 3.4-fold increased risk for the CMV-infected group compared to the non-CMV group. Individuals with IFN-γ +874 AT and AA genotypes exhibited a higher risk of allograft loss. The results of this study suggested that renal transplant recipients with the variant homozygous IFN-γ AA genotype were at risk of CMV infection, whereas the high producer IFN-γ +874 TT genotype appears to be associated with a lower risk of CMV infection (22).

Cytokine Polymorphism and Hepatitis C Virus
An investigation by Allum and colleagues indicated that liver transplant patients with a CC or CT genotype of IL-28B had a lesser chance of graft rejection compared to the TT genotype (62% versus 48%) (23). Interestingly, the positive influence of the CC/CT genotype on reappearance of HCV and the potential of graft rejection were not reliant on antiviral treatment. The authors concluded that unlike the popular notion that donor IL-28B is a predictor of liver transplant success, the recipient's IL-28B status is actually more important in assessing the final outcome of graft survival (23). Similarly, the effect of IL-28B polymorphisms was evaluated in donor and recipient on graft survival during liver transplant. In a cohort of 91 patients with HCV reinfection after liver transplant, genotype rs12979860 CT/TT was identified as a predictor of HCV infection (24).
Allograft cirrhosis was developed in 20% of the patients. Recipients who received a liver from those with epidermal growth factor (EGF) non-AA alleles had an increased graft cirrhosis progression compared to those with an AA allele donor liver (25). An increased rate of sustained virologic response (SVR) was seen in the CC allele of IL-28B compared to non-CC alleles. However, no association was found between the recipient or donor IL-28B and patatin like phospholipase domain containing 3 (PNPLA3) genotype and adverse clinical outcomes (25). In another study, polymorphisms in the IFN-λ4 res368234815 strongly influenced antiviral treatment response. After transplantation, recipient IFN-λ4 genotype TT/TT was associated with a higher SVR rate (26). SVR occurred more in patients receiving a liver from a donor with a favorable genotype, however this result was found to be not statistically significant (26).
HCV RNA clearance induced by antiviral treatment was associated with the cytokine alleles. rs12979860 CC and rs12980275 AA genotype was associated with both end of therapy response (EOTR) and SVR while rs8099917 TT genotype was not associated with SVR but was significantly associated with EOTR (27). Homozygosis of the rs12979860 CC genotype was associated with a positive response to antiviral treatment, suggesting that analyzing IL-28B genotypes might be helpful in order to optimize HCV therapy (27). Patients who did not have the CC genotype of IL-28B but received an IL-28B CC donor liver were found to have a higher chance of achieving SVR than those who obtained a non-CC donor liver. Only 25% of patients achieved SVR if they did not have the CC allele from donor or recipient. Patients also had less fibrosis than recipients with CT and TT genotypes, however, this difference was found not statistically significant. Patient survival did not alter due to IL-28B polymorphism and only 3 patients had graft failures in this study (28). The donor or recipient with rs12979860 CC was also found associated with an increased SVR who were undergoing antiviral treatment (29).
In a study with a Spanish patient cohort, posttransplantation HCV infection was influenced in recipients carrying IL-28B rs12979860 genotype. Forty patients developed severe HCV recurrence while 49 patients did not. It was statistically significant that more patients who had severe HCV recurrence had the TT allele and the T allele was associated with poor outcomes (30). The presence of the T allele in the liver donor had a lower risk of severe HCV recurrence, suggesting its more protective effect concluding that this genetic polymorphism can be a highly reliable predictive indicator of HCV reinfection (30). The authors suggested that the patients who have susceptible genotypes receive prophylactic antiviral treatment in order to improve health outcomes. In one small Egyptian study, IL-28B SNP and preoperative HCV titer predicted post-transplant HCV recurrence and disease-free survival (DFS) while genes in oligoadenylate synthase (OAS) and IL-1B had no association with DFS (30). Those with the CC genotype of IL-18B had higher rates of DFS after transplantation. Patients who had the IL-28B CT and TT alleles were more likely to develop HCV infection recurrence than those with the CC genotype. IL-1B polymorphism was not associated with HCV recurrence post transplantation (31).
The SVR rate was higher in donor grafts who had the TT genotype (73.3%) compared to TG+ GG group (20%) in this small Japanese study (32). Similar results were observed in another larger Japanese study where presence of the major allele (TT) in either the recipient or the donor was found to be associated with an SVR of 53% and 48%, respectively. The minor allele (TG or GG) was found to be associated with an SVR of 26% and 32%, respectively (33). On the other hand, SVR was determined to be higher in recipients with CC genotypes and when receiving grafts from CC genotype donors (34). Recipients with the TT and CT genotype had a shorter time to HCV recurrence within 5 years compared to the CC genotype, 100%, 87%, and 78%, respectively in this study (35). Donor genotype was not found associated with time to recurrence. The rate of SVR was associated with the recipient and donor IL-28B genotype. Recipients with the CC or CT genotype had a higher SVR rate than those with the TT genotype, 58%, 47%, 0%, respectively. Donors with the CC or CT genotype had similar rates. Rates were highest in those who had both matching donor and recipient CC genotype. Patients with the TT genotype or those who received a donor liver from a TT genotype did not attain SVR. Polymorphisms in IL-28B were predictive of fibrosis. Recipients with the TT genotype (32%) had faster fibrosis formation after one year of transplantation (35). These results were also confirmed in a cohort study done in the United States among 255 patients that underwent liver transplantation with HCV. Both recipient and donor CC genotype favored SVR (36).
Polymorphisms of IL-10 and their association with disease progression were investigated in a Polish patient cohort of 196 individuals (37). SNPs such as 1082(A/G) rs1800896, 819(C/T) rs1800871, 592(C/A) rs1800872 and +4529(A/G) rs3024498 in the promoter region of IL-10 gene were investigated. The abundance of ACCA, ATAA, GCCA and GCCG haplotypes were recognized in >5% of individuals. The C allele of 592(C/A) SNP was related to liver inflammation and appeared to be protective, whereas ACCA and ACC haplotype were related to SVR and had lower potential to relapse (37). Genetic variations in the IL-28B gene were related to up to two-fold change in the treatment outcome in individuals with European ancestry and African-Americans. The formation and level of IFNλs were measured to be higher in hepatocytes of HCV-inflicted patients and were associated with a positive IL-28B genotype and treatment outcome. For the rs12979860 genotypes, patients with two favorable response alleles (CC) had a higher probability of SVR to peginterferon alpha (PEG-IFN-α) and ribavirin (RBV) (38).

Cytokine Polymorphism and Hepatitis B Virus
In a cohort of 200 HBV individuals, the SNPs of IL-18 gene (rs187238 and rs1946518) and IL-28B (rs8099917) were studied in the Chinese Han population (39). The abundance of IL-18 SNPs was similar between recipient and donor in relapsing or non-relapsing HBV individuals. The authors found that the circulating IFN-λ levels were lower in HBV patients with relapse history compared to the nonrelapsing patients (39). Interestingly, the IL-28B rs8099917 was associated with elevated alanine transaminase (ALT) and aspartate transaminase (AST) in HBV liver transplant individuals. Similarly, graft recipient individuals with allele G, and both the GG and GT genotypes, experienced elevated ALT and AST levels. The patients with genetic variants of IL-28B eventually had more hepatic dysfunction from HBV infection (39). The presence of SNPs of IL-28B (rs12979860, rs12980275, rs8099917) had a direct influence on serum ALT activity and the viral load in HBVinfected patients in the authors' previous investigation. There is strong evidence to suggest that rs8099917 G allele is a predictor of hepatic injury after liver transplantation and that patients with this variant should be observed for potential future relapse (40).
Lower platelet counts may be beneficial to HBVrelated recipients as it plays a role in liver recovery. Genetic variants of IL-28B may influence liver function recovery as the rs12979860 T allele and rs8099917 C allele have higher peripheral platelet counts after transplantation in the third and fourth day (41). IL-28B protective genotypes, rs12979860 CC allele and rs8099917 AA allele, had significantly lower platelet levels in the first 4 days after transplantation. Abbott and colleagues reported two polymorphisms, namely, a microsatellite change in the +875 IFN-γ CA Allele and a SNP in the +A874T, in the intron 1 of the IFN-γ gene. Both of the variants have been attributed to elevated IFN-γ formation which can lead to different clinical characteristics. In a study involving Polynesian women, the microsatellite and the SNP variants had a strong effect on unfolding innate immune responses in HBV patients (42). Similarly, a remarkable distinction was identified in the abundance of IFN-γ polymorphisms between HBV-infected versus healthy patients (43). The authors did not observe any significant dissimilarity in the HBV infection outcomes due to TNF-α, IL-6 and IL-10 polymorphisms (42). IL-6 gene polymorphism is another potential predictor of HBV prognosis, including hepatocellular carcinoma (HCC) (43). Chen and colleagues suggested that liver donors with rs2069852 AA variants are associated with HCC relapse and the reference SNP could work as a strong predictor of HCC relapse and shorter life expectancy following transplantation in the Chinese Han population (44).

DISCUSSION
Solid organ transplantations are a lifesaving procedure for those with chronic and end stage diseases and it can improve the quality of life of the recipient. However, there can be complications associated with transplants that further increase the risk of graft rejection, morbidity, and mortality for the patient. Risk factors such as age, immunosuppression and genetic composition can further complicate the development and progression of viral infection. In this review, we have investigated thirty-one studies related to various cytokine gene polymorphisms to determine if they influence CMV, HBV, and HCV infection risk in renal and liver transplant recipients. The results were consistent in demonstrating a relationship between cytokine gene polymorphisms and risk of viral infection. The findings of this systematic review suggest that gene polymorphism may be associated with a higher risk of viral infections, except in one instance when the cytokine variant form afforded lower risk of infection, in renal and liver transplant patients.
While eliciting the immune response, the cytokines can exert pro-inflammatory or antiinflammatory functions in organ recipients (7). In the context of the current work, IL-1B, IL-6, IL-12 and IL-18 have pro-inflammatory actions, whereas IFNλ-based genes (IL-28B) and IL-10 are antiinflammatory in nature. The IL-1B and IL-18 cytokines are involved in generating complex cytotoxic actions through inflammation. IL-10 is a master regulator of anti-inflammatory and immunosuppressive actions and provides a protective role in hepatic viral infections and posttransplant infections (19, 20). Whereas IL-28B is part of the cluster of genes known as type III interferons or IFN-λ3, which is associated with comprehensive antiviral and cytotoxic actions (45).
In the patients who have undergone renal transplants, polymorphisms in IL-12, IL-1B, IFN-λ, and PD1 were associated with a higher risk of CMV infection. Individuals with G/-G allele in the IFN-λ cytokine were more prone to developing CMVassociated complications post-transplant. The C allele in the p40 gene of IL-12B was considered to be an independent risk factor for CMV infection in one study, especially in carriers who did not receive antiviral prevention therapy. The A allele was also associated with a higher risk of CMV in those who did not receive prophylaxis therapy. Patients who had the T-allele of IL-28B and carriers of TLR-9 SNP had lower incidences of CMV infection. Polymorphisms in IFN-λ was also studied but it did not prove to be a predictive marker of CMV infection.
Polymorphisms in IL-28B were associated with both the risk of HCV disease pathogenesis and hepatic dysfunction from HBV infection in patients that underwent hepatic transplants. Three studies concluded that the CC genotype in IL-28B was associated with a greater rate of SVR compared to the TT genotype. The -592 C allele in IL-10 cytokine was associated with mild hepatic inflammation when compared to the A allele. Pharmacogenomics is an important aspect of HCV treatment where the genomic polymorphisms of cytokines dominate if an individual is a candidate for PEG-IFN-α and RBV treatment or not. Although, with the advent of newer small molecules drugs for HCV, the PEG-IFN and RBV are losing their place in the clinic. Nevertheless, a large number of HCV patients worldwide are still being treated with the interferonbased regimens.
Similar to HCV, the HBV virus can cause acute and chronic liver issues that can eventually require a liver transplant. Although the discussion on IL-10 started lately, there are few interesting observations about the role of this cytokine in HCV infections. IL-18 is known to be a dominant inflammatory cytokine, which can fight with the HBV and remove it from the host (human) body. IL-18 is one of the cytokines that induces IFN-λ and as a result IL-18 can provide protection from HBV infection. In addition, similar to HCV, IL-28B has a key role in the HBV disease development, progression and graft survival outcomes. Similarly, IFN-λ is a protective cytokine and exerts a strong function on the treatment of HBV infection; the genetic variants of the IFN-λ gene could be a crucial factor in the HBV disease timeline.
The carriers of cytokine polymorphisms demonstrate differential susceptibility to viral infection as well as response from antiviral treatment following liver or kidney transplants. Among the cytokine genes discussed in this study, polymorphisms of IL-28B have reached conclusive implications in the disease pathogenesis and clinical management of viral hepatitis. For the rs12979860 polymorphism of the IL-28B gene, the individuals with the CC genotype had a better prognosis compared to CT or TT genotypes, which essentially drive the organ transplant recipients towards hepatic fibrosis (27, 28). It is plausible that CT or TT genotype carriers express IL-28B protein isoforms that are unable to activate the phosphorylation pathways, leading to removal of the protective effects of IL-28B. According to the guidelines of the Clinical Pharmacogenetics Implementation Consortium, patients with the CC genotype, compared to CT or TT genotypes, have a higher probability of positive treatment outcome from a shorter treatment regimen (24-28 weeks versus 48 weeks) with PEG-IFN-α and RBV (46). Similarly, though the mechanism of this effect is not clear, for the rs8099917 of the IL-28B gene, the TT genotype is hepatoprotective and is considered more desirable for the antiviral treatment (29). Thus, IL-28B genotypes can serve as a robust indicator of therapeutic success in IFN-RBV based treatments of hepatic viral infection. Similarly, the carriers of IL-10 polymorphisms (-592A or -819T) demonstrated improved response to the IFN-RBV regimen (47). It is noteworthy to mention that the basal functions of both IL-28B and IL-10 are anti-inflammatory in nature. In comparison, the polymorphisms of proinflammatory cytokines such as IL-1B (-511 CC) or IL-12 (-1188 CA and CC) actually increased the risk of developing infection in kidney transplant patients (19). We postulate that the variants of IL-1B or IL-12 downregulate the NK cell activation and dampen T cell mediated cytotoxicity, which make the transplant patients more susceptible to viral infection.
Further studies are needed to determine a direct association between CMV, HBV and HCV infections and cytokine polymorphisms. Additional analysis may improve patients' health outcomes and reduce further complications. In the future, immunosuppressive and antiviral therapy can be specifically tailored to patients undergoing transplantation based on cytokine polymorphisms to limit their infection risk. Since cytokines have dual roles of defense and inflammation in the viral infections, the use of antiviral and immunosuppressant medications or the type of medications in transplant patients can be heavily determined by the polymorphic status of their cytokines. The therapeutic outcome or adverse effect landscape of antivirals and immunosuppressants could be affected by the cytokine variant status of a particular patient. The new generation anti-HCV small molecules have become part of the routine treatment in the last five years and the studies on the effect of these cytokine polymorphisms on their small molecule treatment outcome is warranted.
The current study has several limitations. Several studies examined a small sample population and many did not establish statistical significance due to this. Another drawback was that multiple studies primarily examined Caucasian patients despite the genetic variance among different races. Only a handful of studies were multicenter, multinational, or both, thereby limiting the scope of their application. Heterogeneity of studies, a handful of studies with small sample size, and variability in clinical settings all limited our ability to perform a meta-analysis to assess the summary effect of association between cytokine gene polymorphisms and post-transplant CMV, HBV and HCV infection.

CONCLUSIONS
In conclusion, our systematic review has demonstrated that cytokine gene polymorphisms, especially IL-12B and IL-1B, were found to be associated with an increased risk of infection in kidney transplant recipients and IL-28B in liver transplant recipients. These results further confirm the role of cytokine variants in assessing susceptibility to infections, treatment efficacy, and outcomes in renal and liver transplant recipients. It is important for researchers to continue exploring cytokine gene polymorphisms to better inform healthcare providers about their possible role and impact on health outcomes, especially in renal and liver transplant patients, as well as in patients with other disease conditions, to guide their treatment options. The presence of unfavorable SNPs in donor and recipient genotypes may predict a recipient's susceptibility to post-transplant complications. It is important to conduct genetic testing and analyze a patient's cytokine genetic makeup prior to transplantation of an organ from a donor to ensure a favorable genotype which may lead to optimized drug therapy, reduced costs, and better health outcomes.

CONFLICT OF INTEREST
Authors have no financial or any other conflict of interest to declare. Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
3-4, Fig. 1 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Table 1 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

Summary of evidence 24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

18-20
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

20
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

Funding 27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.