Association between E23K variant in KCNJ11 gene and new-onset diabetes after liver transplantation.

New-onset diabetes after transplantation (NODAT) is an important complication after solid organ transplantation. NODAT is a polygenic disease and KCNJ11 E23K polymorphism is considered as a diabetes-susceptibility gene. The present study aimed to assess the association between KCNJ11 (rs5219) variants and the risk of developing NODAT after liver transplantation. This study was conducted on 120 liver transplant recipients who had received tacrolimus-based immunosuppressive drugs. The liver transplant recipients were divided into an new onset diabetes mellitus (NODM) and a non-NODM group. The NODAT group consisted of 60 patients who developed diabetes in the first 6 months after transplantation, while the non-NODAT group included 60 patients who remained euglycemic. The patients were genotyped using polymerase chain reaction-restriction fragment length polymorphism and the incidence of NODAT was compared between the two groups. Nongenetic risk factors including donor gender and cold ischemia time, and recipient (MELD score, presence of viral hepatitis, acute rejection and steroid pulse therapy) were also considered. The KCNJ11 KK variant was associated with an increased risk for NODAT with respective odds ratio of 6.03 (95 % confidence interval 2.37-15.4; P < 0.001]. Donor age and male sex, recipient age as well as fasting plasma glucose before transplantation were significantly different between NODAT and non-NODAT groups (P < 0.05). The prednisolone daily dosage was significantly higher in the NODAT group (P = 0.01). These patients received pulse of methyl prednisolone for treatment of acute rejection. This study showed that polymorphisms in KCNJ11 might predispose the patients treated by tacrolimus to development of NODAT after liver transplantation.

The frequency and distribution of thiopurine S-methyltransferase alleles in south Iranian population.

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathiopurine. Variability in TPMT activity is mainly due to genetic polymorphism. The frequency of the four allelic variants of the TPMT gene, TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B (G460A) and TPMT*3C (A719G) were determined in an Iranian population from south of Iran (n = 500), using polymerase chain reaction (PCR)-RFLP and allele-specific PCR-based assays. Four hundred seventy four persons (94.8%) were homozygous for the wild type allele (TPMT*1/*1) and twenty five people were TPMT*1/*3C (5%). One patient was found to be heterozygous in terms TPMT*1 and *2 alleles with genotype of TPMT*1/*2 (0.2%). None of the participants had both defective alleles. The TPMT*3C and *2 were the only variant alleles observed in this population. The total frequency of variant alleles was 2.6% and the wild type allele frequency was 97.4%. The TPMT*3B and *3A alleles were not detected. Distributions of TPMT genotype and allele frequency in Iranian populations are different from the genetic profile found among Caucasian or Asian populations. Our findings also revealed inter-ethnic differences in TPMT frequencies between different parts of Iran. This view may help clinicians to choose an appropriate strategy for thiopurine drugs and reduce adverse drug reactions such as bone marrow suppression.

Prevalence of GJB2 (CX26) gene mutations in south Iranian patients with autosomal recessive nonsyndromic sensorineural hearing loss.

Hereditary hearing loss is a genetically heterogeneous disorder. Mutations in connexin 26 (CX26), are a major cause in many countries and are largely dependent on ethnic groups. The purpose of our study was to evaluate the prevalence of GJB2 mutations among affected individuals from south of Iran. Fifty patients presenting with autosomal recessive non-syndromic hearing loss from Fars, province in south of Iran, were studied for mutations in GJB2 gene and screened by direct sequencing. Mutations were detected in 15 out of 50 patients (30 %). Eight different mutations were identified; six of them were previously identified (35delG, V27I M34V, V153I, A149T, V198M). The remaining two alleles, L28I and N169T, were novel variants. The most common mutations were 35delG followed by V153I with an allele frequency of 7 and 6 %, respectively. In this study, 30 % of our subjects were found to have the causative variants or polymorphisms in GJB2 and the c.35delG mutation was the most common cause in our patients. However, more study with larger sample size as well as in vitro functional study for these new variants in Xenopus oocytes is required.

The Impact of HLA-G and HLA-E Polymorphisms on CMV Reinfection in Liver Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV) reinfection in transplant patients has been associated with graft loss and decreased patient survival. In this regard, the HLA-G molecule has the immunomodulatory characteristic and its soluble isoforms have important roles in immunity to viruses. The 14bp insertion/deletion polymorphism impacts HLA-G mRNA stability. Regarding the HLA-E molecule, two nonsynonymous alleles, HLA-E*0101, and HLA-E*0103 are different in their functions including the affinity of the relative peptide. OBJECTIVE: To explore the possible link between HLA-G and HLA-E polymorphisms with CMV reinfection among liver transplant recipients (LTRs). METHODS: In this study, a total of 140 liver transplantations were performed; of which 70 CMV-reactivated LTRs and 70 CMV non-reactivated ones were recruited. The cut-off value of CMV DNA was determined to be 100 copies/mL. PCR evaluated different genotypes for HLA-G and ARMS-PCR for HLA-E*0101 and *0103. RESULTS: Neither the HLA-G genotypes (-14 bp/-14bp and +14bp/+14 bp homozygous genotypes with the p-values: 0.43, and 0.13, respectively +14 bp/-14 bp heterozygous genotype with p-value: 0.49) nor the HLA-E genotypes (HLA-E*0101/0103, HLA-E*0101/0101, and HLA-E*0103/0103 with the p-values: 0.152, 0.249, and 0.391, respectively) had any association with CMV reinfection in the LTRs. CONCLUSION: No difference was observed in the HLA-E and HLA-G genotype frequencies between our studied groups. Further studies are needed to explore other genetic variations and evaluate soluble HLA-G and HLA-E levels in the transplant population.

Study the polymorphism of CYP3A5 and CYP3A4 loci in Iranian population with laryngeal squamous cell carcinoma.

Cancer reflects a complicated network of interactions between genes and environmental factors. Cytochrome P450 (CYP) is a multi-gene superfamily participating in the metabolism of xenobiotics. The aim of our study was to examine whether polymorphisms in the CYP enzyme genes affect the risk of developing larynx squamous cell carcinoma (SCC). Polymorphism of CYP3A5 and CYP3A4 genes were investigated in 50 patients with laryngeal SCC and 100 control subjects by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). In patients the CYP3A5 3/3 and 1/3genotypes were detected in 92% and 8% respectively. There was no relation between genotype, allele frequency and grade/stage of tumor. In control group, the frequency of CYP3A5 3/3 and CYP3A5 1/3 genotype were 98% and 2% respectively. There was no significant difference in genotype and allele frequency of this gene between patient and control group. In respect of CYP3A41A/B, people in both patient and control groups had the same genotype of CYP3A41A/1A. In this study, the CYP gene variants were not associated with increased risk of laryngeal SCC. Study on the other genetic factors which are involved in activation/detoxication of procarcinogenes, such as CYP1A1, CYP1B1, CYP2E1 and gluthation S transferase is recommended.

Frequency of HLA-G exon 8 polymorphisms and kidney allograft outcome in Iranian population.

The 14-bp polymorphism in exon 8 of the HLA-G gene is associated with HLA-G mRNA stability and the patterns of alternative isoform splicing and may influence the functionality of the HLA-G molecule. HLA-G expression was related to allograft acceptance and fewer episodes of acute rejection during heart, kidney and liver-kidney transplantation. In order to determine a possible correlation between the 14-bp insertion/deletion polymorphism and kidney allograft outcome in our population, genomic DNA was isolated from 144 patients who had received isolated kidney allografts. The recipients was divided into two groups, grafts presenting features of rejection group and a non-rejection group, and compared them with a control group of 100 healthy subjects. There was no significant difference in allelic frequencies of 14-bp insertion/deletion polymorphism between normal controls and kidney transplant patients. No significant difference was found between the RG and the NRG regarding the 14-bp genotypes and alleles. Therefore, additional studies with more sample size from other populations with analysis of other HLA-G polymorphisms are necessary to define this polymorphism as a valuable clinical marker.

Influence of glutathione S-transferase M1 and T1 polymorphisms with acute rejection in Iranian liver transplant recipients.

Glutathione-S-transferase (GST) has a major protective role against free radicals and plays a vital role in phase II of biotransformation of many substances. In liver transplantation, reperfusion injury, calcineurin drug consumption and infection produce free radicals that cause tissue injury and organ damage. Genetic variations of GST may influence individual susceptibility to some diseases associated with the deleterious effects of oxidative metabolism. Although it is well known that the rejection is an immunological process, however, in this study, we have investigated the gene frequency and relationship between human GST gene polymorphism and rejection in liver transplant recipients. We have assessed 51 liver transplant recipients from Shiraz, South of Iran. The GSTT1 and GSTM1 genotypes were identified by polymerase chain reaction (PCR). The gene frequency of GSTM1 and GSTT1 polymorphism were evaluated. We observed that GSTM1 null genotype was present in 68.62% of the liver transplant recipients while GSTT1 null genotype was present in 37.25% of the liver transplant subjects. There was a trend between increasing age and acute rejection episode. No statistically significant correlation was present between GSTM1 null and GSTT1 null genotypes with an acute rejection episode in transplant recipients. No relationship was observed between GST genotypes and acute rejection. It is likely that development and progression of rejection are determined by genes which is involved in immunological pathways rather than genes that is participated in free radicals destruction. However, these findings need to be confirmed in a larger series of patients.

Interleukin-7 receptor-alpha gene polymorphisms in bone marrow transplant recipients.

Graft-versus-host disease is the main complication after hematopoietic stem cells transplantation (HSCT). Non-HLA genotypes, such as cytokines, have been investigated for their potential roles in the occurrence and severity of GVHD as well as for their contribution to overall transplant-related mortality and survival. IL-7 which is secreted by bone marrow stromal cells plays an important role in the development and survival of T cells. Its effect is mediated via interleukin 7 receptor (IL7R). This study investigates the possible links between IL-7alphaR single nucleotide polymorphisms (+510 C/T, +1237 A/G, +2087 T/C and +3110A/G) and transplant outcomes among 116 recipients of HSCT. Genotypes were determined using polymerase chain reaction-sequence-specific primers. No significant differences were observed between the genotypic distributions of IL-7alphaR polymorphisms and incidence of acute or chronic graft versus host disease. Additional studies with larger sample are necessary to further define the influence of IL-7alphaR on the immune response after bone marrow transplantation.

Vitamin D receptor genotypes and kidney allograft rejection.

OBJECTIVE: Transplantation of renal grafts is an established treatment for renal failure in a variety of medical conditions. Polymorphisms in genes, coding for proteins involved in immune response, may influence immunological and non-immunological mechanisms that lead to allograft loss. Vitamin D receptor (VDR) agonist has been shown to reduce short and long term allograft rejection in animal model. There are functional polymorphisms in VDR gene. MATERIALS AND METHODS: A total of 75 renal allograft recipients with at least 2 years follow-up were selected and genotyped for two polymorphisms in the VDR genes (FokI and BsmI) and the association of each genotype with renal allograft survival and acute rejection was evaluated. RESULTS: We are unable to find statistically significant association between any of the study polymorphisms and clinical outcomes. CONCLUSION: We have found no evidence to suggest that either VDR FokI or BsmI polymorphism determines the incidence of acute rejection or graft survival after renal transplantation. A larger sample size is necessary to confirm these findings.

Influence of recipient and donor IL-10, TNFA and INFG genotypes on the incidence of acute renal allograft rejection.

OBJECTIVE: Transplantation of renal grafts is an established treatment for renal failure in a variety of medical conditions. Acute allograft rejection remains an important cause of morbidity after kidney transplantation, and has been shown to be a crucial determinant of long-term graft function. Although rejection is mediated by recipient lymphocytes, both donor and recipient factors contribute to the local environment that influences the severity of rejection response. Because cytokines are the main components of immune responses, we evaluate single nucleotide polymorphisms (SNP) of several cytokine genes that may influence the production of a given cytokine and therefore the features of immune reactions. MATERIAL AND METHODS: The aim of this study was to determine the impact of the cytokine gene polymorphism of pro and anti-inflammatory cytokines on the development of acute allograft rejection, which could be used in pretransplant patient assessment. Three SNPs including IL-10 (-1082 G/A), TNFA (-308 G/A), and INFG (+874 T/A) were analyzed in 46 patients with acute allograft rejection, 54 patients with stable graft function and their kidney donors by PCR-ARMS method. RESULTS: We are unable to find statistically significant association between any of the studies polymorphisms and clinical outcomes. CONCLUSION: We have found no evidence to suggest that either recipient or donor cytokines polymorphisms determine the incidence of acute rejection after renal transplantation. Our observation, however, is based on few cases, and this may mask a possible favorable effect. It is recommended that several functionally related genes should be tested in similar studies, since this approach has a higher chance to detect genetic risk factors than the screening of single genetic variants.

Modification of Diet in Renal Disease equation underestimates glomerular filtration rate in Egyptian kidney donors.

OBJECTIVES: Inulin clearance and radioisotope studies are the most accurate means of measuring glomerular filtration rates (GFRs). The Kidney Disease Outcomes Quality Initiative guidelines recommend estimating GFRs with the Modification of Diet in Renal Disease (MDRD) or the Cockcroft- Gault equation. We examined the accuracy of the MDRD equation and creatinine clearance based on 24-hour urine collection to predict GFRs in a group of healthy donors. MATERIALS AND METHODS: We examined the medical records of 100 kidney donors who had undergone 99mTc-diethylenetriamine-pentaacetic acid (DTPA) renal clearance and creatinine clearance measurements at the transplant outpatient clinic of Cairo University Hospital in Cairo, Egypt, between June 2002 and July 2006. GFR was predicted with the abbreviated MDRD formula. We examined significant differences, potential correlations, and agreements between GFR as predicted and as measured. RESULTS: The mean eGFRMDRD was 8.16% lower than the 99mTc-DTPA GFR (116.11 -/+ 25.44mL/min/1.73m2 vs 126.32 -/+ 24.21 mL/min/1.73 m2; difference range, -84 to +61 mL/min/1.73 m2; P = .002). Creatinine clearance was 13.14% higher than the 99mTc-DTPA GFR (142.90 -/+ 27.51 mL/min/1.73 m2; difference range, +65 to -60 mL/min/1.73 m2; P < .001). A significant positive correlation was observed when creatinine clearance and 99mTc-DTPA-measured GFR were compared (R=0.451; P = .000). No significant correlation was noted between eGFRMDRD and 99mTc-DTPA-measured GFRs (R=0.126; P = .211). A Bland-Altman analysis showed poor agreement between GFRMDRD and creatinine clearance on the one hand and measured GFR on the other. CONCLUSIONS: Neither the MDRD equation nor creatinine clearance is accurate in predicting GFRs in healthy donors.

Polymorphism of the methylenetetrahydrofolate reductase C677T gene with chronic allograft nephropathy in renal transplant recipients.

OBJECTIVES: This study sought to investigate the frequency of the 5, 10-methylenetetrahydrofolate reductase gene (MTHFR C677T) in 127 patients (77 with chronic allograft nephropathy and 50 with normal renal function) who had undergone a renal transplant at least 20 months earlier to define the risk factors for chronic allograft dysfunction. Fifty healthy subjects served as controls. MATERIALS AND METHODS: Genotypes were determined using polymerase chain reaction followed by restriction fragment length polymorphism analysis. The restriction enzyme for the MTHFR C677T variants was HinfI. RESULTS: No statistically significant differences were seen between the allelic and genotypic distribution of the MTHFR polymorphism. CONCLUSIONS: Additional studies with larger sample sizes are needed to define the influence of MTHFR C677T genotyping on clinical outcomes in renal allograft recipients.

Interleukin-10 gene polymorphism in bone marrow transplant recipients.

OBJECTIVES: Graft-versus-host disease is the main complication after hematopoietic stem cell transplant, occurring even after donor and recipient human leukocyte antigen matching, apparently because of donor/recipient minor histocompatibility antigen mismatches and cytokine polymorphisms. Interleukin-10 suppresses several activities of the immune response by inhibiting T helper 1 and T helper 2 cells. These properties suggest that interleukin-10 could act as a suppressive mediator and prevent graft-versus-host disease. This study evaluates the association between the interleukin-10 promoter gene polymorphism and transplant outcomes among 18 recipients of cytokine-mobilized peripheral blood stem cells from human leukocyte antigen-matched sibling donors. MATERIALS AND METHODS: We analyzed 3 single nucleotide polymorphisms in the proximal region of the interleukin-10 promoter gene (-1082/-819/-592) by the amplification refractory mutation system and polymerase chain reaction-restriction fragment length polymorphism methods. Eighteen donors and their recipients who had undergone an allogeneic peripheral blood stem cell transplant at the Bone Marrow Transplant Center in Nemazi Hospital (Shiraz, Southern Iran) between September 2005 and September 2006 were enrolled. RESULTS: The GCC haplotype (1082G/819C/592C) was predominant in both the donor and the recipient, but no significant correlations were present between the GCC haplotype in either the donor or the recipient and the risk of acute graft-versus-host disease (P = .56). CONCLUSIONS: The interleukin-10 promoter gene polymorphism was found not to be associated with acute graft-versus-host disease in patients after an allogeneic peripheral blood stem cell transplant from human leukocyte antigen-matched sibling donors. Additional studies with larger samples are necessary to further define the influence of interleukin-10 on the immune response after bone marrow transplant.

Influence of p53 (rs1625895) polymorphism in kidney transplant recipients.

Reperfusion injury predisposes the kidney allograft to acute rejection. Apoptosis is a mechanism that results in graft injury, and TP53 is an important involved gene. To determine the association between single nucleotide polymorphism (SNP) in the pro-apoptotic protein p53 (rs1625895) and acute rejection in renal transplants, we studied 100 recipients of kidney allografts and 100 healthy individuals served as controls. The polymorphism was determined by the polymerase chain reaction restriction-fragment length polymorphism (PCR-RFLP) test. Overall, 31 recipients developed rejection. There was no difference in the genotype frequencies between the recipients and the controls. However, we found a difference of genotype and allele frequencies between recipients with and those without rejection. The WW genotype was more frequent in recipients with rejection. Although rejection is a complex immunologic event and functional importance of SNPs has not been confirmed yet, we suggest that wild type p53 may promote apoptosis during inflammation.

HLA-G polymorphism (rs16375) and acute rejection in liver transplant recipients.

BACKGROUND: HLA-G molecules exhibit immunomodulatory properties that can delay graft rejection. The 14 bp insertion/deletion polymorphism (INDEL) (rs16375) influences the stability of final HLA-G mRNA and its soluble isoforms. OBJECTIVE: The present study aimed to investigate the possible association between this polymorphism and the incidence of acute rejection in Iranian liver transplant recipients. METHODS: Different genotypes were evaluated by PCR. The patients who had acute rejection within 6 months after transplantation were classified as acute rejection (AR) group, while others were considered as nonacute rejection (NAR) group. RESULTS: Among the recipients, 21 patients (21%) had at least one episode of AR, while the other 79 patients (79%) had normal liver function. No significant differences were found between the two groups regarding sex, MELD score, and primary liver disease. Also, no difference was observed concerning rs16375 genotype and allele frequency (P = 0.44, OR: 0.69; CI: 0.21-2.10). CONCLUSION: The study results revealed no significant difference between the AR and the NAR groups regarding the 14 bp INDEL genotypes and alleles. Further studies are recommended to be conducted on other polymorphic sites as well as monitoring of serum HLA-G concentration in order to ascertain the potential implications of this marker in our population.

Human islet cell isolation: the initial step in an islet transplanting program in Shiraz, Southern Iran.

OBJECTIVES: Type 1 diabetes mellitus is an emerging epidemic worldwide and results from autoimmune destruction of insulin-producing ß cells. Islet transplanting is a potential treatment for type 1 diabetes mellitus. MATERIALS AND METHODS: The Shiraz Organ Transplant Center is a leading center for organ transplants, especially pancreatic transplants, in Iran. For this reason, we want to establish an islet transplanting program. Here, we briefly describe our experience with islet isolation on 6 pancreata from deceased donors. We discussed the necessary equipment required for this procedure, as well as the professionals needed and a specially planned facility. RESULTS: Islet yield was ≤ 100 000 (islet equivalent), viability 40% to 45%, and the purity was 30% to 45%. We do not have a refrigerated COBE processor for purification; therefore, the yield was low. Our experience shows that we should improve things, so as to acquire more islets for developing clinical grade cell therapy. CONCLUSIONS: Overall, isolation costs are high, and accessing a safer, more economic, and persistent source of material and reagents will improve this technique.

Influence of endothelial nitric oxide synthase gene polymorphisms (-786T/C, 4a4b, 894G/T) on Iranian kidney transplant recipients.

OBJECTIVES: Nitric oxide is a major mediator in vascular biology and regulator of regional blood flow. Its production is catalyzed by the enzyme endothelial nitric oxide synthase. Protective actions of nitric oxide in ischemia and reperfusion are due to its potential as an antioxidant and anti-inflammatory agent, along with its inhibitory effects on cell signaling pathways of nuclear proteins, such as NF-kB. The endothelial nitric oxide synthase gene polymorphisms affect endothelial nitric oxide synthase activity and are associated with endothelial dysfunction. This study sought to examine the association between single nucleotide polymorphisms in endothelial nitric oxide synthase gene (rs 2070744, 27VNTR, and rs1799983) and the development of acute rejection in renal transplant patients. MATERIALS AND METHODS: Sixty-six renal transplant recipients (33 patients with an episode of acute rejection and 33 recipients an episode of acute rejection), between June 2010 and March 2011, were included. The polymorphism was determined by simple polymerase chain reaction and polymerase chain reaction-restriction fragment-length polymorphism analysis. RESULTS: There was only a significant association of endothelial nitric oxide synthase -786T allele and acute rejection (P = .03). Recessive model of T-786C alleles (TT vs TC+CC) and acute rejection confirmed a significant association (odds ratio: 3.12; 95% CI: 0.01-9.83; P = .025). Haplotype CbG was higher in recipients without rejection as compared to rejection group (OR: 0.42, 95% CI: 0.16-1.13; P < .05). Respecting the endothelial nitric oxide synthase gene 894G/T single nucleotide polymorphisms and 27VNTR, no significant association between the allele/genotype and acute rejection was seen. CONCLUSION: Recipient endothelial nitric oxide synthase gene polymorphisms do not alter the risk of acute rejection after a renal transplant. Rejection is a complex immunologic event. Therefore, finding associated genetic variants demands a multicentric larger sample size.

The interleukin-6 and vascular endothelial growth factor in hematopoietic stem cell transplantation.

We studied the correlation between changes in the serum levels of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) with complications such as acute graft versus host disease (aGVHD), veno-occlusive disease (VOD) or occurrence of infection after hematopoietic stem cell transplantation (HSCT). Serum VEGF and IL-6 levels were sequentially measured by enzyme-linked immunosorbant assay (ELISA) in 35 patients who had undergone HSCT. Serum levels of IL-6 in patients with aGVHD were increased in comparison with patients without aGVHD, but the difference was not statistically significant. Serum levels of VEGF were only increased in patients with aGVHD during the early days after transplantation. No significantly altered levels of IL-6 and VEGF were observed in patients with VOD or sepsis. These results demonstrate that rising levels of VEGF and IL-6 may be good and specific biomarkers for transplant aGVHD.

Association between tacrolimus concentration and genetic polymorphisms of CYP3A5 and ABCB1 during the early stage after liver transplant in an Iranian population.

OBJECTIVES: Tacrolimus is widely used as an immunosuppressive drug in liver transplant recipients with a narrow therapeutic range and variable individualized pharmacokinetics. Tacrolimus is a substrate of cytochrome P-450 3A enzyme and the drug transporter, P-glycoprotein. MATERIALS AND METHODS: We determined the genotypic frequencies of cytochrome P-4503A5 (rs776746), and ABCB1 (rs1045642), single nucleotide polymorphisms in a population of 100 Iranian liver transplant patients, and investigated the influence of the above-mentioned single nucleotide polymorphisms on tacrolimus concentrations. At 7 and 30 days after transplant, tacrolimus dosages (mg/kg/d), trough blood levels (T0), and dose-adjusted concentrations (concentration/dosage ratio) were determined. Polymerase chain reaction, followed by restriction fragment length polymorphism analysis, was used for genotyping cytochrome P-4503A5*3 [6986A>G] as well as ABCB1 [3435C>T]. RESULTS: Ninety-five percent of the population showed a cytochrome P-4503A5*3/*3 genotype. ABCB13435TT genotype was observed in 33 cases (33%); whereas 51 cases (51%) carried 3435CT, and 16 cases (16%) carried 3435CC. With regard to the ABCB1 and cytochrome P-4503A5, they showed no influence on tacrolimus dosing requirements at 1 week or 1 month after transplant. No association of any genetic variant with the acute rejection rate was found. CONCLUSIONS: Finally, as the liver donor genotype influences tacrolimus pharmacokinetics with regard to expression of cytochrome P-4503A5, far more than the genotype of the recipient; therefore, it should be considered before recommending any personal immunosuppressive treatment based on pharmacogenetics.

Thiopurine S-methyltransferase polymorphism in Iranian kidney transplant recipients.

OBJECTIVES: Thiopurine S-methyltransferase is an enzyme that catalyzes S-methylation of azathioprine as an immunosuppressive drug. Genetic polymorphisms influence thiopurine S-methyltransferase activity. There are 3 variant alleles: thiopurine S-methyltransferase*2, *3A, and *3C are responsible for more than 95% cases of low-enzyme activity. MATERIALS AND METHODS: We studied these polymorphisms and the occurrence of azathioprine adverse effects in 50 renal transplant recipients undergoing triple immunosuppressive therapy including azathioprine, cyclosporine, and prednisone. Thiopurine S-methyltransferase genetic polymorphism was determined by polymerase chain reaction restriction fragment length polymorphism assay and allele-specific polymerase chain reaction methods. Azathioprine dosage; leukocyte, erythrocyte, and platelet counts; and graft rejection episodes were analyzed during hospitalization. RESULTS: Two patients (2%) were heterozygous for thiopurine S-methyltransferase*3C, the remaining patients were thiopurine S-methyltransferase wild-type *1/*1 (98%). Thiopurine S-methyltransferase wild-type homozygous and heterozygous patients were administered similar azathioprine dosages at the beginning of treatment (2.42 ± 0.50 and 2.52 ± 0.40 mg/kg/24 h). During subsequent days, mean azathioprine dosage administered to thiopurine S-methyltransferase wild-type homozygous patients was similar to heterozygous patients, but with no statistical difference (P = .28). Three patients had an acute rejection episode during this time. Five patients (10%) had reduced azathioprine dosage owing to adverse effects. Adverse reactions consisted of hematotoxicity (n=2), hepatotoxicity (n=1), and gastrointestinal toxicity (n=2). All recipients were wild-type homozygotes. CONCLUSIONS: The frequency of thiopurine S-methyltransferase gene mutations is low among our patients. The incidence of adverse reactions to azathioprine was also low, even in patients carrying a variant of thiopurine S-methyltransferase. We conclude that determining thiopurine S-methyltransferase genotype is not useful in our population to predict adverse reactions to azathioprine.