Brief Article Open Access
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Feb 28, 2012; 18(8): 847-854
Published online Feb 28, 2012. doi: 10.3748/wjg.v18.i8.847
Interleukin-10-1082G/A polymorphism and acute liver graft rejection: A meta-analysis
Fei Liu, Bo Li, Wen-Tao Wang, Yong-Gang Wei, Lv-Nan Yan, Tian-Fu Wen, Ming-Qing Xu, Jia-Yin Yang
Fei Liu, Bo Li, Wen-Tao Wang, Yong-Gang Wei, Lv-Nan Yan, Tian-Fu Wen, Ming-Qing Xu, Jia-Yin Yang, Department of Liver and Vascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Author contributions: Liu F and Li B designed the study, collected and analyzed the data and wrote the manuscript; Wang WT and Wei YG collected and analyzed the data and wrote the manuscript; Yan LN analyzed the data and contributed to the discussion; Wen TF and Xu MQ revised the manuscript; Yang JY contributed to the discussion.
Correspondence to: Wen-Tao Wang, Professor, MD, Department of Liver and Vascular Surgery, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu 610041, Sichuan Province, China. cdwangwentao@163.com
Telephone: +86-28-85422476 Fax: +86-28-85423724
Received: May 25, 2011
Revised: September 2, 2011
Accepted: October 28, 2011
Published online: February 28, 2012

Abstract

AIM: To investigate the association between interleukin (IL)-10-1082 (G/A) promoter polymorphism and acute rejection (AR) in liver transplant (LT) recipients.

METHODS: Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine Databases. Summary odds ratios (ORs) and 95% CIs for IL-10-1082 G/A polymorphism and AR were calculated in a fixed- and a random-effects model as appropriate.

RESULTS: This meta-analysis included seven case-control studies, which comprised 652 cases of LT recipients in which 241 cases developed AR and 411 cases did not develop AR. Overall, the variant A allele was not associated with AR risk when compared with the wild-type G allele (OR = 0.94, 95% CI: 0.64-1.39). Moreover, similar results were observed when the AA genotype was compared with the AG/GG genotype (OR = 1.05, 95% CI: 0.55-2.02). When stratifying for ethnicity, no significant association was observed among either Caucasians or Asians. Because only one study was performed in Asian patients, the result of subgroup analysis by ethnicity would not be reliable for Asians. Limiting the analysis to the studies with controls in the Hardy-Weinberg equilibrium, the results were persistent and robust. No publication bias was found in the present study.

CONCLUSION: This meta-analysis suggests that IL-10-1082 G/A polymorphism may be not associated with AR risk in LT recipients among Caucasians.

Key Words: Liver transplantation, Acute rejection, Interleukin-10, Gene polymorphism, Meta-analysis



INTRODUCTION

Liver transplantation is regarded as an effective therapeutic option for end-stage liver disease as survival after liver transplantation has dramatically improved during the last two decades. Despite this success, graft dysfunction occurs in up to 13% of the patients during the first year after transplantation and rises to 35% in 5 years[1,2]. Acute rejection (AR) and recurrence of disease are two major immunological complications, which may lead to graft dysfunction. The inflammatory microenvironment within the graft may play a role in the precipitation of rejection[3], although the underlying mechanisms involved in such events remain unclear. A network of short-acting cytokines and growth factors in turn determines this environment. Cytokines have a central role in the immunologic events that occur after transplantation and are intimately implicated in graft rejection.

Interleukin-10 (IL-10), whose encoding gene is located on chromosome 1 (1q31-1q32), is an immunoregulatory cytokine produced by Th2 cells, monocytes/macrophages, and regulatory T cells, and is capable of downregulating T-cell activation and major histocompatibility complex expression on antigen-presenting cells in vitro[4]. Previous studies have suggested that IL-10 mRNA levels are increased just before a rejection episode[5]. The production of cytokines (including IL-10) is under genetic control and varies among individuals as a function of polymorphisms within the regulatory regions of the various genes that determine the transcriptional activation[6-9]. The promoter of the IL-10 gene contains three biallelic polymorphisms at positions -1082 (base G to A, dbSNP no. rs1800896), -819 (base C to T, dbSNP no. rs1800871), and -592 (base C to A, dbSNP no. rs1800872) from the transcription start site, and these influence the capacity of cells to produce IL-10[10]. For example, the G-to-A polymorphism at position -1082 of the IL-10 promoter reduces IL-10 production[7]. Alloimmune responses and variations in susceptibility to rejection may be influenced by individual variations in cytokine genes. Associations between cytokine gene polymorphisms and rejection of kidney[11,12], heart[13], and lung[14] have been reported.

Over the last two decades, a number of studies have assessed the association between the IL-10-1082 (G/A) promoter polymorphism and AR in liver transplant (LT) recipients in different populations; however, the results are inconsistent and inconclusive[15-22]. In 2005, Warlé et al[23] published findings from a meta-analysis of the IL-10-1082 (G/A) polymorphism and AR risk in LT recipients (based on five studies). The pooled results by Warlé et al[23] suggested that the IL-10 polymorphism at position -1082 was a genetic risk factor for acute liver graft rejection, and that LT recipients carrying the IL-10-1082. A allele displayed a lower rejection rate. However, this manuscript had some limitations mainly due to the small sample size and data retrieval. In order to derive a more comprehensive estimation of the association between IL-10-1082 polymorphism and AR risk in LT recipients, we conducted a meta-analysis to re-evaluate the association.

MATERIALS AND METHODS
Literature search strategy

We searched the PubMed, Embase, CNKI (China National Knowledge Infrastructure) and Chinese Biomedicine databases for all articles on the association between IL-10 polymorphisms and AR risk in LT recipients (last search update 20th March 2011). The following key words were used: “interleukin-10” or “IL-10”; “acute rejection” or “early graft rejection”; “liver transplantation”. The search was performed without restriction on language, but conducted on human subjects. The reference lists of reviews and retrieved articles were hand searched at the same time. We did not consider abstracts or unpublished reports. If more than one article was published by the same author using the same case series, we selected the study where the most individuals were investigated.

Inclusion and exclusion criteria

We reviewed abstracts of all citations and retrieved studies. The following criteria were used to include published studies: (1) evaluation of the association between IL-10-1082 G/A polymorphism and AR in LT recipients; (2) a case-control or cohort design; and (3) sufficient genotype data presented to calculate the odds ratio (OR) with 95% confidence interval (CI). Major reasons for exclusion of studies were: (1) duplicate data; (2) an abstract, comment, review or editorial; and (3) no sufficient data were reported.

Data extraction

Two investigators (Liu F and Li B) extracted information from all eligible publications independently according to the inclusion criteria listed above. Disagreements were resolved by discussion between the two investigators. The following information was collected from each study: first author, year of publication, transplant period, indication for transplantation, patient characteristics (age, gender, etc), definition of AR, immunosuppressive regimen, country of the first or corresponding author, ethnicity, number of AR cases and controls (non-AR), genotyping methods and evidence of Hardy-Weinberg equilibrium (HWE). Ethnicities were categorized as Asian or Caucasian.

Statistical analysis

We first assessed HWE in the controls for each study using the goodness-of-fit test (χ2 or Fisher’s exact test) and a P < 0.05 was considered as significant disequilibrium. The strength of the association between AR and the IL-10-1082 G/A polymorphism was estimated using the OR and corresponding 95% CI. For the -1082G/A polymorphism, we estimated the risk of the variant A allele compared with the wild-type G allele, and then evaluated the risk of AA vs (AG + GG) which assumed a recessive effect of the variant A allele. We also carried out the stratified analyses by ethnicity (Caucasians/Asians) and HWE in controls (yes/no).

Both the Cochran Q statistic[24] to test for heterogeneity and the I2 statistic to quantify the proportion of the total variation due to heterogeneity[25] were calculated. A P value of more than the nominal level of 0.10 for the Q statistic indicated a lack of heterogeneity across studies, allowing for the use of a fixed-effects model (the Mantel-Haenszel method)[26]; otherwise, the random-effects model (the DerSimonian and Laird method) was used[27]. Sensitivity analysis was performed to assess the reliability of the results.

Several methods were used to assess potential publication bias. Visual inspection of funnel plot asymmetry was conducted. The Begg’s rank correlation method[28] and the Egger’s weighted regression method[29] were used to statistically assess publication bias (P < 0.05 was considered statistically significant). All analyses were done using STATA software, version 11.0 (STATA Corp., College Station, TX, United States). All the P values were two-sided.

RESULTS
Characteristics of studies

There were 59 papers relevant to the search words. Via steps of screening the title and reading the abstract, 10 studies were identified[15-22,30,31]. Of these, three studies were excluded (two did not report the association between IL-10-1082 G/A polymorphism and AR in LT recipients[22,30]; two articles[20,31] were published by a different first author using the same case series, and we selected the latest study[20]); thus, seven studies[15-21] which included 241 AR cases and 411 non-AR cases were found to match our inclusion criteria. The flow chart of selection of studies and reasons for exclusion is presented in Figure 1. Characteristics of studies included in the meta-analysis are presented in Tables 1 and 2.

Table 1 Baseline characteristics of studies included in the meta-analysis.
Ref.Transplant periodIndications for transplantationPatients characteristics (age, gender)Definition of acute rejectionImmunosuppression regimens
Bathgate et al[21]1992-1998ALD, PBC, PSC, chronic viral hepatitis, acute liver failure, autoimmune hepatitis, otherNot describedLiver biopsy and treatment with high- dose steroidsCsA/tacrolimus + prednisone + azathioprine
Tambur et al[20]Not describedHepatitis B and/or hepatitis C, PBC, PSC, cryptogenic, other20-69 yr, M/F: 32/36Liver biopsy (AR within first 6 wk)CsA/tacrolimus + prednisone with or without azathioprine.
Warlé et al[18]1992-1999Hepatitis B, hepatitis C, PBC, PSC, ALD, otherAR group: 47 ± 11 yr, M/F: 22/19 Non-AR group: 49 ± 12 yr, M/F: 20/28Liver biopsy and treatment with high-dose steroids (AR within first 4 wk)CsA/tacrolimus + prednisone Maintain target therapeutic blood levels of 100-200 ng/mL for CsA or 5-10 ng/mL for tacrolimus
Fernandes et al[19]Not describedNot described19-73 yr, M/F: 26/27Liver biopsy and treatment with high- dose steroidsTacrolimus + prednisolone
Mas et al[17]1999-2000Hepatitis B, Hepatitis C, PSC, HCC, ALD, Cryptogenic, other24-60 yr, M/F: 44/33Liver biopsy (AR within first 8 wk)CsA/tacrolimus + steroids + MMF
Karasu et al[16]2002-2003Viral, nonviralAR group: 44.4 ± 12.7 yr, M/F: 17/9 Non-AR group: 37.4 ± 11.8 yr, M/F:11/6Treatment with high-dose steroids (AR within first 8 wk)CsA/tacrolimus+steroids Maintain target therapeutic blood levels of 5-10 ng/mL for tacrolimus
Xie et al[15]2003-2005HBV-related cirrhosis, HBV-related HCC, fulminant hepatitis BAR group: 43.6 ± 9.0 yr, M/F: 35/6 Non-AR group: 46.5 ± 9.0 yr, M/F:130/15Liver biopsy (AR within first 4 wk)CsA/tacrolimus + prednisolone + MMF
Figure 1
Figure 1 Flow chart of selection of studies and specific reasons for exclusion from the meta-analysis.
Table 2 Characteristics of studies included in the meta-analysis.
Ref.CountryEthnicityNo. ofCaseControlGenotyping methodsHWE in controls
case/controlAAAG/GGAAAG/GG
Bathgate et al[21]United KingdomCaucasian68/7616522254PCR-SSPYes
Tambur et al[20]IsraelCaucasian33/3019141416PCR-SSPNo
Warlé et al[18]NetherlandsCaucasian41/486351731ARMS-PCRYes
Fernandes et al[19]United StatesCaucasian13/40491525AS-PCRYes
Mas et al[17]United StatesCaucasian19/551271243DNA-sequencingYes
Karasu et al[16]TurkeyCaucasian26 /17121489PCR-SSPYes
Xie et al[15]ChinaAsian41/14536512817PCR-RFLPYes
Figure 2
Figure 2 Odds ratios and 95% CI of individual studies and pooled data for the association of the interleukin-10-1082 G/A polymorphism and acute rejection comparing A allele with G allele. OR: Odds ratios.

There were six studies of Caucasian descendents, one study of Asian descendents. Studies had been carried out in China, Turkey, the United States, Netherlands, Israel and the United Kingdom. All studies defined rejection as biopsy-proven episodes of AR during the early posttransplant period (AR within first 4-8 wk), treated with high-dose steroids, except for the study of Karasu et al[16]. Immunosuppressive regimens in all studies consisted of a calcineurin inhibitor (cyclosporin or tacrolimus) and prednisone with or without azathioprine. Mycophenolate mofetil was only used in a subgroup of patients studied by Xie et al[15] and Mas et al[17]. Most studies extracted DNA from peripheral blood, and only two studies[15,17] from surgically explant liver tissue from recipients. Several genotyping methods were used, including PCR-RFLP, PCR-SSP, direct sequencing, ARMS-PCR and AS-PCR. The genotype distributions among the controls of all studies were consistent with HWE except for Tambur’s study[20].

Quantitative synthesis

Overall, the variant A allele was not associated with AR risk when compared with the wild-type G allele (ORrandom = 0.94, 95% CI: 0.64-1.39, Pheterogeneity = 0.07) (Figure 2). When the AA genotype was compared with AG/GG genotype (recessive model), no significant association was observed (ORrandom = 1.05, 95% CI: 0.55-2.02, Pheterogeneity = 0.01) (Figure 3). When stratified for ethnicity, no significant association was observed among either Caucasians or Asians (for Caucasians: A allele vs G allele, ORrandom = 0.95, 95% CI: 0.61-1.47, Pheterogeneity = 0.04; AA vs AG/GG, ORrandom = 1.07, 95% CI: 0.49-2.32, Pheterogeneity = 0.01; for Asians: A allele vs G allele, ORrandom = 0.96, 95% CI: 0.34-2.68; AA vs AG/GG, ORrandom = 0.96, 95% CI: 0.33-2.77). Because only one study was performed in Asian patients, the result of subgroup analysis by ethnicity could not be reliable for Asians.

Figure 3
Figure 3 Odds ratios and 95% CI of individual studies and pooled data for the association of the interleukin-10-1082 G/A polymorphism and acute rejection comparing AA genotype with AG/GG Genotype. OR: Odds ratios.

In Tambur’s study, the distribution of IL-10-1082 genotypes among controls was not in HWE. Limiting the analysis to the studies within HWE, the estimated association remained unchanged (A allele vs G allele, ORfixed = 0.81, 95% CI: 0.61-1.07, Pheterogeneity = 0.13; AA vs AG/GG, ORrandom = 0.98, 95% CI: 0.46-2.11, Pheterogeneity = 0.009).

Publication bias

Begg’s funnel plot and Egger’s test were performed to evaluate the publication bias of studies of AR in LT recipients. Figures 4 and 5 display funnel plots that examined the IL-10-1082 polymorphism and overall AR risk included in the meta-analysis. The shape of funnel plots did not reveal any evidence of funnel plot asymmetry. The statistical results did not show publication bias (A allele vs G allele: Begg’s test P = 0.55, Egger’s test P = 0.26; AA vs AG/GG: Begg’s test P = 0.76, Egger’s test P = 0.67).

Figure 4
Figure 4 Begg’s funnel plot of interleukin-10-1082 G/A polymorphism and acute rejection risk in liver transplant recipients (AA vs AG/GG). OR: Odds ratios.
Figure 5
Figure 5 Egger’s publication bias plot of interleukin-10-1082 G/A polymorphism and acute rejection risk in liver transplant recipients (AA vs AG/GG).
DISCUSSION

In spite of major advances in the field of immunosuppressive therapy, acute hepatic allograft rejection remains an important problem after liver transplantation. Almost 30%-50% of patients experience at least one episode of rejection within the first year[32]. Cytokines, a group of small, soluble, or cell membrane-bound protein or glycoprotein molecules, play an essential role in the regulation of inflammatory and immune responses. Despite the many variables that influence acute rejection, previous reports indicate that cytokine genotypes that result from polymorphisms can sometimes correlate with acute allograft rejection[33,34]. Alloimmune responses and variations in susceptibility to rejection may be influenced by individual variations in cytokine genes. An association between susceptibility to graft rejection and polymorphism in cytokine gene promoters in kidney, heart, lung, and bone marrow recipients has been reported by some centers[11-14,35], although others have not confirmed this[36-38].

IL-10 is an antiinflammatory cytokine, which can inhibit the production of tumor necrosis factor-α, IL-1, IL-6, IL-8, and IL-12 in monocytes/macrophages and interferon-γ in T cells[4]. Therefore, in the context of allograft rejection, local IL-10 release may have inhibitory properties on macrophages, T cells, and cytokines. However, the role of IL-10 in LT patients remains controversial. For example, some studies have suggested that IL-10 mRNA levels are increased just before a rejection episode[5], while others have indicated that IL-10 levels are unchanged during rejection of the LT[39]. In animal models, overexpression of IL-10 by gene transfer prolonged graft survival of orthotopic LTs[40]. Since some studies[33,34] reported that cytokine genotypes that result from polymorphisms can sometimes correlate with acute allograft rejection, a number of studies have assessed the association between the IL-10-1082 promoter polymorphism and AR in LT recipients in different populations. However, some of the results were conflicting, even in the same population, and thus a systematic review and meta-analysis of the association between IL-10-1082 G/A polymorphism and AR risk was of great value.

A meta-analysis can overcome some problems caused by a single study, such as small sample size, low test power and selection bias; however, some concerns have to be addressed before aggregating data. First, the definition of AR, as the main outcome measure for this analysis, should be consistent among included studies. In six studies, AR was defined as “early” biopsy-proven AR within the first 4-8 wk after liver transplantation, treated with high-dose steroids. However, Karasu et al[16] defined AR as an increase in liver enzymes in the absence of vascular or biliary problems, associated with an improvement after treatment by increasing the dose of immunosuppressive drugs or pulse steroid therapy within the first 8 wk. In the overall meta-analysis performed in this study, the number of patients from the Karasu et al[16] study is small, suggesting that this factor probably had little effect on the overall estimates. Moreover, the immunosuppressive regimen among different studies included is also an important factor which should be addressed. All LT patients included in this meta-analysis received more or less the same type of immunosuppression: a calcineurin inhibitor and prednisone, with or without azathioprine. However, there were some differences in the type of induction therapy, dosages and maintenance of target levels in blood, which can provide a possible explanation for significant heterogeneity in a recessive model.

This meta-analysis was based on seven case-control studies and showed that IL-10-1082 G/A polymorphism was not associated with the risk of AR in LT recipients. Our result is not consistent with a previous systemic review[23]. This is most probably because the previous meta-analysis had a relatively small sample size (the Warlé et al[23] meta-analysis included only five studies for IL-10-1082 G/A polymorphism and AR risk in LT recipients) and may have generated a very rough risk estimate. The G-to-A polymorphism at position -1082 of the IL-10 promoter reduces IL-10 production[7], and individuals with the IL-10-1082-GG genotype showed the greatest IL-10 production after in vitro stimulation, whereas IL-10-1082-GA and -AA showed intermediate and low production, respectively[7,41]. Moreover, previous studies[42,43] showed that Th2 cytokines, such as IL-10, are associated with graft tolerance. Therefore, it can be deduced that patients with an IL-10 genotype corresponding to low IL-10 production are more susceptible to rejection, whereas the IL-10 genotype corresponding to high production is found mainly among nonrejectors. However, our result is inconsistent with the above hypotheses. This is probably because the notion, derived mainly from animal studies, that IL-10 has a role in human allograft tolerance needs re-evaluation. In addition, since the effect of the IL-10-1082 promoter polymorphism on in vitro and thus in vivo cytokine production is still inconclusive[7,44,45], its biological effect on acute liver graft rejection remains speculative.

As previously described, ethnicity can strongly influence the distribution of cytokine gene polymorphisms[46]. In Caucasian patients[17], the IL-10 AA genotype at position -1082 occurred in 32.5%, while among Asian patients[15] it occurred in 88.2%. Therefore, there may be different associations between IL-10-1082 promoter polymorphism and AR in LT recipients among different ethnicities. Nevertheless, our results were inconsistent with our hypothesis. When stratifying for ethnicity, no significant association was observed among either Caucasians or Asians. The null result may be due to the limited number of studies with only one study (based on Asian patients) available in this meta-analysis, and there is a very high risk of reporting bias for the relationship of the IL-10-1082 G/A polymorphism and AR risk in the Asian population. In future, additional studies based on Asian patients should be performed to re-evaluate the association between IL-10-1082 G/A polymorphism and AR risk in this population.

It seemed that selection bias could have played a role because the genotype distribution of -1082 G/A polymorphism among control subjects disobeyed the HWE in one study[20]. It is widely believed that deviation from HWE may be due to genetic reasons including non-random mating, or the alleles reflect recent mutations that have not reached equilibrium, as well as methodological reasons including biased selection of subjects from the population or genotyping errors[47,48]. Apart from the reasons for disequilibrium, the results of genetic association studies might be spurious if the distribution of genotypes in the control groups were not in HWE[49,50]. Thus we carried out subgroup analysis by HWE in controls. When excluding the study that was not within HWE, the estimated pooled OR did not change at all, suggesting that this factor probably had little effect on the overall estimates.

However, there some limitations remain in this meta-analysis: (1) our meta-analysis was based on unadjusted OR estimates because not all published studies presented adjusted ORs or when they did, the ORs were not adjusted by the same potential confounders, such as age, sex, ethnicity and exposures. Lack of the information for the data analysis may cause serious confounding bias; (2) there was significant between-study heterogeneity from studies of the IL-10-1082 G/A polymorphism, and the genotype distribution also showed deviation from HWE in one study; (3) the number of studies and the number of subjects in the studies included in the meta-analysis were small; (4) we must emphasize the fact that this meta-analysis adds more studies and increases the sample size but that it is an update that is not important because it adds patients (small importance); it is important because the statistical analysis reflects that IL-10 polymorphisms are not relevant in AR in liver transplantation; and (5) meta-analysis is retrospective research that is subject to methodological limitations. In order to minimize bias, we developed a detailed protocol before initiating the study, and performed a meticulous search for published studies by using explicit methods for study selection, data extraction and data analysis. Nevertheless, our results should be interpreted with caution.

In conclusion, this meta-analysis suggests that IL-10-1082 G/A polymorphism may be not associated with AR risk in LT recipients among Caucasians. Since only one study was from an Asian population, it is critical that larger and well-designed multicenter studies based on Asian patients should be performed to re-evaluate the association.

COMMENTS
Background

Interleukin (IL)-10 is an antiinflammatory cytokine, which can inhibit the production of tumor necrosis factor-alpha, IL-1, IL-6, IL-8 and IL-12 in monocytes/macrophages and interferon-γ in T cells. Therefore, in the context of allograft rejection, local IL-10 release may have inhibitory properties on macrophages, T cells, and cytokines. The production of cytokines (including IL-10) is under genetic control and varies among individuals as a function of polymorphisms within the regulatory regions of the various genes that determine the transcriptional activation. The G-to-A polymorphism at position -1082 of the IL-10 promoter reduces IL-10 production. Alloimmune responses and variations in susceptibility to rejection may be influenced by individual variations in cytokine genes.

Research frontiers

To date, a number of studies (including meta-analysis) have assessed the association between the IL-10 1082 G/A polymorphism and acute rejection (AR) risk in liver transplant (LT) recipients among different populations; however, the results are inconsistent and inconclusive.

Innovations and breakthroughs

Contrary to the finding of the previous meta-analysis, this study suggests that IL-10-1082 G/A polymorphism may be not associated with AR risk in LT recipients among Caucasians.

Applications

It can be seen from this paper that IL-10-1082 G/A polymorphism could not alter susceptibility to AR risk in LT recipients. It suggests that a common variant in the functional region of a meaningful gene had little effect on human disease.

Peer review

This appears to be a well-done meta-analysis study.

Footnotes

Peer reviewers: Satoshi Yamagiwa, MD, PhD, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan; Valentin Fuhrmann, MD, Department of Internal Medicine 4, Intensive Care Unit, Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; Virendra Singh, MD, DM, Additional Professor, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India

S- Editor Tian L L- Editor Cant MR E- Editor Zhang DN

References
1.  Yu AS, Ahmed A, Keeffe EB. Liver transplantation: evolving patient selection criteria. Can J Gastroenterol. 2001;15:729-738.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Keeffe EB. Patient selection and listing policies for liver transplantation. J Gastroenterol Hepatol. 1999;14 Suppl:S42-S47.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Jazrawi SF, Zaman A, Muhammad Z, Rabkin JM, Corless CL, Olyaei A, Biggs A, Ham J, Chou S, Rosen HR. Tumor necrosis factor-alpha promoter polymorphisms and the risk of rejection after liver transplantation: a case control analysis of 210 donor-recipient pairs. Liver Transpl. 2003;9:377-382.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 20]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
4.  Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683-765.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4364]  [Cited by in F6Publishing: 3987]  [Article Influence: 218.2]  [Reference Citation Analysis (0)]
5.  Platz KP, Mueller AR, Rossaint R, Steinmüller T, Lemmens HP, Lobeck H, Neuhaus P. Cytokine pattern during rejection and infection after liver transplantation--improvements in postoperative monitoring? Transplantation. 1996;62:1441-1450.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 42]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
6.  Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA. 1997;94:3195-3199.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1541]  [Cited by in F6Publishing: 1412]  [Article Influence: 64.2]  [Reference Citation Analysis (0)]
7.  Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet. 1997;24:1-8.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1221]  [Cited by in F6Publishing: 1139]  [Article Influence: 122.1]  [Reference Citation Analysis (0)]
8.  Kroeger KM, Carville KS, Abraham LJ. The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol. 1997;34:391-399.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 619]  [Cited by in F6Publishing: 170]  [Article Influence: 25.8]  [Reference Citation Analysis (0)]
9.  Bouma G, Crusius JB, Oudkerk Pool M, Kolkman JJ, von Blomberg BM, Kostense PJ, Giphart MJ, Schreuder GM, Meuwissen SG, Peña AS. Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease. Scand J Immunol. 1996;43:456-463.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 274]  [Cited by in F6Publishing: 260]  [Article Influence: 11.0]  [Reference Citation Analysis (0)]
10.  Perrey C, Pravica V, Sinnott PJ, Hutchinson IV. Genotyping for polymorphisms in interferon-gamma, interleukin-10, transforming growth factor-beta 1 and tumour necrosis factor-alpha genes: a technical report. Transpl Immunol. 1998;6:193-197.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Pelletier R, Pravica V, Perrey C, Xia D, Ferguson RM, Hutchinson I, Orosz C. Evidence for a genetic predisposition towards acute rejection after kidney and simultaneous kidney-pancreas transplantation. Transplantation. 2000;70:674-680.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 78]  [Cited by in F6Publishing: 70]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
12.  Sankaran D, Asderakis A, Ashraf S, Roberts IS, Short CD, Dyer PA, Sinnott PJ, Hutchinson IV. Cytokine gene polymorphisms predict acute graft rejection following renal transplantation. Kidney Int. 1999;56:281-288.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Azzawi M, Hasleton PS, Turner DM, Yonan N, Deiraniya AK, Sinnott PJ, Hutchinson IV. Tumor necrosis factor-alpha gene polymorphism and death due to acute cellular rejection in a subgroup of heart transplant recipients. Hum Immunol. 2001;62:140-142.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 4]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
14.  Lu KC, Jaramillo A, Lecha RL, Schuessler RB, Aloush A, Trulock EP, Mendeloff EN, Huddleston CB, Alexander Patterson G, Mohanakumar T. Interleukin-6 and interferon-gamma gene polymorphisms in the development of bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2002;74:1297-1302.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 53]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
15.  Xie HY, Wang WL, Yao MY, Yu SF, Feng XN, Jin J, Jiang ZJ, Wu LM, Zheng SS. Polymorphisms in cytokine genes and their association with acute rejection and recurrence of hepatitis B in Chinese liver transplant recipients. Arch Med Res. 2008;39:420-428.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 23]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
16.  Karasu Z, Ulukaya S, Ayanoglu HO, Basturk B, Ulukaya E, Akyildiz M, Tokat Y. Cytokine gene polymorphism and early graft rejection in liver transplant recipients. Transplant Proc. 2004;36:2791-2795.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 9]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
17.  Mas VR, Fisher RA, Maluf DG, Archer KJ, Contos MJ, Mills SA, Shiffman ML, Wilkinson DS, Oliveros L, Garrett CT. Polymorphisms in cytokines and growth factor genes and their association with acute rejection and recurrence of hepatitis C virus disease in liver transplantation. Clin Genet. 2004;65:191-201.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Warlé MC, Farhan A, Metselaar HJ, Hop WC, Perrey C, Zondervan PE, Kap M, de Rave S, Kwekkeboom J, Ijzermans JN. Cytokine gene polymorphisms and acute human liver graft rejection. Liver Transpl. 2002;8:603-611.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 36]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
19.  Fernandes H, Koneru B, Fernandes N, Hameed M, Cohen MC, Raveche E, Cohen S. Investigation of promoter polymorphisms in the tumor necrosis factor-alpha and interleukin-10 genes in liver transplant patients. Transplantation. 2002;73:1886-1891.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 42]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
20.  Tambur AR, Ortegel JW, Ben-Ari Z, Shabtai E, Klein T, Michowiz R, Tur-Kaspa R, Mor E. Role of cytokine gene polymorphism in hepatitis C recurrence and allograft rejection among liver transplant recipients. Transplantation. 2001;71:1475-1480.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 58]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
21.  Bathgate AJ, Pravica V, Perrey C, Therapondos G, Plevris JN, Hayes PC, Hutchinson IV. The effect of polymorphisms in tumor necrosis factor-alpha, interleukin-10, and transforming growth factor-beta1 genes in acute hepatic allograft rejection. Transplantation. 2000;69:1514-1517.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 77]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
22.  Jonsson JR, Hong C, Purdie DM, Hawley C, Isbel N, Butler M, Balderson GA, Clouston AD, Pandeya N, Stuart K. Role of cytokine gene polymorphisms in acute rejection and renal impairment after liver transplantation. Liver Transpl. 2001;7:255-263.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 23]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
23.  Warlé MC, Metselaar HJ, Hop WC, Tilanus HW. Cytokine gene polymorphisms and acute liver graft rejection: a meta-analysis. Liver Transpl. 2005;11:19-26.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 41]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
24.  Cochran WG. The combination of estimates from different experiments. Biometr. 1954;10:101-129.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2911]  [Cited by in F6Publishing: 1230]  [Article Influence: 43.4]  [Reference Citation Analysis (0)]
25.  Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-560.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719-748.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-188.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088-1101.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9307]  [Cited by in F6Publishing: 4345]  [Article Influence: 358.0]  [Reference Citation Analysis (0)]
29.  Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-634.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Li D, Zhu JY, Gao J, Wang X, Lou YQ, Zhang GL. Polymorphisms of tumor necrosis factor-alpha, interleukin-10, cytochrome P450 3A5 and ABCB1 in Chinese liver transplant patients treated with immunosuppressant tacrolimus. Clin Chim Acta. 2007;383:133-139.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 26]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
31.  Mor E, Klein T, Shabtai E, Ben-Ari Z, Ortegel JW, Micowitz R, Tur-Kaspa R, Tambur AR. Cytokine gene polymorphism in liver allograft recipients. Transplant Proc. 2001;33:2941-2942.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 1]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
32.  Wiesner RH, Demetris AJ, Belle SH, Seaberg EC, Lake JR, Zetterman RK, Everhart J, Detre KM. Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome. Hepatology. 1998;28:638-645.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 360]  [Cited by in F6Publishing: 262]  [Article Influence: 15.7]  [Reference Citation Analysis (0)]
33.  Turner D, Grant SC, Yonan N, Sheldon S, Dyer PA, Sinnott PJ, Hutchinson IV. Cytokine gene polymorphism and heart transplant rejection. Transplantation. 1997;64:776-779.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 191]  [Cited by in F6Publishing: 178]  [Article Influence: 8.0]  [Reference Citation Analysis (0)]
34.  Marshall SE, McLaren AJ, Haldar NA, Bunce M, Morris PJ, Welsh KI. The impact of recipient cytokine genotype on acute rejection after renal transplantation. Transplantation. 2000;70:1485-1491.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 54]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
35.  Dugré FJ, Gaudreau S, Belles-Isles M, Houde I, Roy R. Cytokine and cytotoxic molecule gene expression determined in peripheral blood mononuclear cells in the diagnosis of acute renal rejection. Transplantation. 2000;70:1074-1080.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 58]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
36.  Lee H, Clark B, Gooi HC, Stoves J, Newstead CG. Influence of recipient and donor IL-1alpha, IL-4, and TNFalpha genotypes on the incidence of acute renal allograft rejection. J Clin Pathol. 2004;57:101-103.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 24]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
37.  Poole KL, Gibbs PJ, Evans PR, Sadek SA, Howell WM. Influence of patient and donor cytokine genotypes on renal allograft rejection: evidence from a single centre study. Transpl Immunol. 2001;8:259-265.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 9]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
38.  Bijlsma FJ, Bruggink AH, Hartman M, Gmelig-Meyling FH, Tilanus MG, de Jonge N, de Weger RA. No association between IL-10 promoter gene polymorphism and heart failure or rejection following cardiac transplantation. Tissue Antigens. 2001;57:151-153.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 17]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
39.  Bishop GA, Rokahr KL, Napoli J, McCaughan GW. Intragraft cytokine mRNA levels in human liver allograft rejection analysed by reverse transcription and semiquantitative polymerase chain reaction amplification. Transpl Immunol. 1993;1:253-261.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 46]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
40.  Shinozaki K, Yahata H, Tanji H, Sakaguchi T, Ito H, Dohi K. Allograft transduction of IL-10 prolongs survival following orthotopic liver transplantation. Gene Ther. 1999;6:816-822.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 36]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
41.  Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology. 1999;30:526-530.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 301]  [Cited by in F6Publishing: 276]  [Article Influence: 13.7]  [Reference Citation Analysis (0)]
42.  Dallman MJ. Cytokines as mediators of organ graft rejection and tolerance. Curr Opin Immunol. 1993;5:788-793.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 8]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
43.  Mottram PL, Han WR, Purcell LJ, McKenzie IF, Hancock WW. Increased expression of IL-4 and IL-10 and decreased expression of IL-2 and interferon-gamma in long-surviving mouse heart allografts after brief CD4-monoclonal antibody therapy. Transplantation. 1995;59:559-565.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Cartwright NH, Keen LJ, Demaine AG, Hurlock NJ, McGonigle RJ, Rowe PA, Shaw JF, Szydlo RM, Kaminski ER. A study of cytokine gene polymorphisms and protein secretion in renal transplantation. Transpl Immunol. 2001;8:237-244.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Warlé MC, Farhan A, Metselaar HJ, Hop WC, Perrey C, Zondervan PE, Kap M, Kwekkeboom J, Ijzermans JN, Tilanus HW. Are cytokine gene polymorphisms related to in vitro cytokine production profiles? Liver Transpl. 2003;9:170-181.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Hoffmann SC, Stanley EM, Cox ED, DiMercurio BS, Koziol DE, Harlan DM, Kirk AD, Blair PJ. Ethnicity greatly influences cytokine gene polymorphism distribution. Am J Transplant. 2002;2:560-567.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Mitchell AA, Cutler DJ, Chakravarti A. Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test. Am J Hum Genet. 2003;72:598-610.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Hosking L, Lumsden S, Lewis K, Yeo A, McCarthy L, Bansal A, Riley J, Purvis I, Xu CF. Detection of genotyping errors by Hardy-Weinberg equilibrium testing. Eur J Hum Genet. 2004;12:395-399.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Salanti G, Amountza G, Ntzani EE, Ioannidis JP. Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur J Hum Genet. 2005;13:840-848.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP. Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol. 2006;163:300-309.  [PubMed]  [DOI]  [Cited in This Article: ]