Role of interleukin-21 and interleukin-21 receptor polymorphisms in the treatment of HBeAg-positive chronic hepatitis B patients with peginterferon.
ABSTRACT: The aim of this study was to evaluate the relationship between interleukin-21 (IL-21) and interleukin-21 receptor (IL-21R) polymorphisms and the response to peginterferon alfa (PEG-IFN ?) therapy in HBeAg-positive chronic hepatitis B (CHB) patients.A total of 143 HBeAg-positive CHB patients treated for 48 weeks with PEG-IFN ? and followed up for 24 weeks post-treatment were retrospectively evaluated. Genotypes analysis was performed for IL-21 polymorphisms rs907715, rs2221903, and IL-21R polymorphisms rs3093301 and rs2285452. Serum IL-21 levels were measured by enzyme-linked immunosorbent assay.The end of virological response (EVR) rate was 46.9% (67/143) at the end of treatment, the sustained virological response (SVR) rate was 43.4% (62/143) and the complete response (CR) rate was 32.1% (46/143) at 24 weeks post-treatment. Patients who carried IL-21 rs 2221903 genotype AA had a rather higher rate of EVR (response rate: 52.4%, odds ratio [OR] 0.42, 95% confidence interval [CI]: 0.19-0.91, P?=?.021), SVR (response rate: 47.6%, OR 0.43, 95% CI: 0.19-0.95, P?=?.028), and CR (response rate: 38.1%, OR 0.31, 95% CI: 0.12-0.79, P?=?.014) when compared to those had AG genotype. Meanwhile, IL-21rs 2221903 genotype AA was also independently associated with markedly reduced HBsAg levels (>1og10?IU/mL) after 24 weeks treatment and low HBsAg levels (<100?IU/mL) at the end of treatment. IL-21 rs907715 AG/GG genotype was independently associated with SVR (OR: 2.92, 95% CI: 0.98-8.6, P?=?.039; OR: 3.23, 95% CI: 1.0-10.4, P?=?.039). Patients with IL-21 rs907715 AG/GG genotype had higher serum IL-21 levels than those with rs907715 AA genotype (P?=?.021).IL-21 rs2221903 and rs907715 polymorphisms were significantly associated with the treatment response to PEG-IFN ? among Chinese HBeAg-positive CHB patients.
Project description:BACKGROUND:The single nucleotide polymorphisms of interleukin-21 (IL-21) gene were confirmed to be related to various diseases, but no studies have examined the possible role of IL-21 single nucleotide polymorphisms (SNPs) (rs907715, rs2221903, and rs12508721) in gastric precancerous lesions. AIM:To explore the associations between SNPs of IL-21 gene (rs907715, rs2221903, and rs12508721) and gastric precancerous lesions in a Chinese population. METHODS:Three SNPs of IL-21 were genotyped using polymerase chain reaction-ligase detection reaction in 588 cases and 290 healthy controls from May 2013 to December 2016 in northwestern China. Gastric precancerous lesions were confirmed by endoscopic examination and categorized as non-atrophic gastritis, atrophic gastritis, and intestinal metaplasia. Descriptive statistic and logistic regression were used for data analyses. RESULTS:IL-21 rs907715 genotype CC and C frequencies were higher in in patients with gastric precancerous lesions than in the controls (OR = 1.59, 95%CI: 1.06-2.38, P = 0.013; OR = 1.28, 95%CI: 1.01-2.22, P = 0.044, respectively) after adjusting for confounding factors. For SNP rs907715 in intestinal metaplasia patients, significant differences between cases and controls were observed in the frequencies of genotype CC and C (OR = 1.92, 95%CI: 1.24-2.98, P = 0.004; OR = 1.53, 95%CI: 1.04-2.24, P = 0.028, respectively); for non-atrophic gastritis and atrophic gastritis patients, the CC and C genotypes showed no significant association with risk in all models. No association between either rs2221903 or rs12508721 and gastric precancerous lesions was found in the present study. In the haplotype analysis, the TC haplotype (rs907715 and rs12508721) and TT haplotype (rs2221903 and rs907715) were more frequent in the case group than control group (P < 0.05). CONCLUSION:Our findings indicate that SNP rs907715 of IL-21 gene is associated with gastric precancerous lesions. The TC haplotype (rs907715 and rs12508721) and TT haplotype (rs2221903 and rs907715) increased the risk of gastric precancerous lesions. If confirmed, these findings will shed light on the etiology of precancerous lesions.
Project description:BACKGROUND:We investigated the relationship between hepatitis B virus (HBV)-related pathogenesis and single nucleotide polymorphisms (SNPs) in interleukin-21 (IL-21)-JAK-STAT signaling pathway genes. METHODS:We used the high-resolution melting (HRM) method to genotype five SNPs (IL-21 rs2221903, IL-21 rs4833837, IL-21 receptor (IL-21R) rs2285452, JAK3 rs3008, and STAT3 rs1053023) in 546 HBV-infected patients and 353 healthy Chinese subjects. The HBV-infected patients were further divided into subgroups based on the HBV-related pathologies: chronic hepatitis B (CHB), HBV-related liver cirrhosis (LC), and HBV-related hepatocellular carcinoma (HCC). RESULTS:There were no significant differences in the genotype and allele distributions of the five SNPs between the HBV-infected patients and healthy subjects. The genotype and allele frequencies were similar in the two groups for IL-21 rs2221903 (A>G, P = 0.83 and 0.67), rs4833837 (A>G, P = 0.80 and 0.49), IL-21R rs2285452 (G>A, P = 0.25 and 0.68), STAT3 rs1053023 (A>G, P = 1.00 and 0.96), and JAK3 rs3008 (C>T, P = 0.32 and 0.54). However, patients with the IL-21R rs2285452 AA genotype were more susceptible to HBV-related HCC than those with the IL-21R rs2285452 GA/GG genotype (P = 0.03, OR = 3.27, 95% CI = 1.16-9.20). The serological marker model of "HBsAg+, HBeAg+, HBcAb+" was predominant among patients with HBV infection. However, there was no association between the genotype's distribution of the five SNPs and the serological marker models (P > 0.05). CONCLUSIONS:These findings demonstrate that the IL-21R rs2285452 AA genotype increases the risk of HBV-related HCC in Chinese patients.
Project description:The etiology of lung cancer is still incompletely understood. Previous studies have suggested the association between IL-21 polymorphisms and autoimmune diseases, however, little is known about its role in lung cancer susceptibility. Here, we investigated the role of two SNPs of IL-21 gene in a cohort of non-small cell lung cancer (NSCLC) patients. A total of 128 NSCLC patients and 156 healthy controls were genotyped. Multivariate logistic regression was used to analyze the association between IL-21 polymorphisms and NSCLC risk. Our data showed that both rs907715 and rs2221903 were significantly associated with lung cancer susceptibility, and patients carrying rs907715A (P = 0.007, adjusted OR = 0.60, 95% CI = 0.42-0.87) or rs2221903G (P = 0.020, adjusted OR = 0.52, 95% CI = 0.30-0.90) allele had a decreased risk of NSCLC. Further study identified that the association between IL-21 polymorphisms and NSCLC risk was limited to lung adenocarcinoma. Haplotype analysis revealed that the AG (P = 0.006, OR = 0.072 95% CI = 0.011-0.451) and AA (P = 0.022, OR = 0.657, 95% CI = 0.458-0.941) haplotypes of rs907715/rs2221903 were associated with a decreased risk of NSCLC, whereas the GA (P = 0.0001, OR = 1.932, 95% CI = 1.378-2.710) haplotype was associated with an increased risk. In conclusion, our study demonstrates the association between IL-21 polymorphisms (rs907715 and rs2221903) and NSCLC risk in a Chinese Han population, indicating their potential role in lung cancer detection and treatment.
Project description:BACKGROUND: The abnormality of interleukin-21 (IL-21)-IL-21-receptor (IL-21R) system has been found in many autoimmune diseases including autoimmune thyroid diseases (AITDs). In this study, we investigated whether polymorphisms of the IL-21 and IL-21R are associated with Graves' disease (GD) and Hashimoto's thyroiditis (HT), two major forms of AITDs, among a Chinese population. METHODS: Rs907715, rs4833837, rs2221903 and rs2055979 of the IL-21 gene and rs3093301 and rs2285452 of the IL-21R gene were explored in a case-control study including 405 GD, 228 HT patients and 242 controls. These genes were genotyped by the PCR and restriction fragment length polymorphism (RFLP) analysis and the MASS spectrometry method. RESULTS: For IL-21 gene, we identified and confirmed a higher prevalence of A alleles of rs2221903 (P?=?0.018, OR?=?1.50 95% CI?=?1.07-2.09) in GD patients. We also found a significant association between rs2221903 and HT (allele: P?=?0.009, OR?=?1.69 95% CI?=?1.13-2.51; genotype: recessive P?=?0.021, OR?=?11.72 95% CI?=?1.46-94.13). For the IL-21R gene, compared with controls, the genotype frequencies of rs3093301 and rs2285452 were significantly different in HT patients using dominant genetic model (P?=?0.023, OR?=?1.61 95% CI?=?1.07-2.42; P?=?0.031, OR?=?1.71 95% CI?=?1.05-2.80, respectively). Furthermore, the haplotype AA containing the major alleles of rs4833837 and rs2221903 was associated with increased susceptibility to GD with an OR of 1.50(95% CI =1.08-2.09, P?=?0.016), and to HT with an OR of 1.69(95% CI =1.14-2.52, P?=?0.009). CONCLUSION: Our results indicated that the SNPs of the IL-21 gene is associated with the development of GD. In addition, we found that individuals with the SNPs of the common IL-21 and IL-21R may have higher risk of HT.
Project description:To investigate the relationship between interleukin-21 (IL21) gene polymorphisms and chronic hepatitis B virus (HBV) infection in a Chinese population.In this case-control study, 366 Chinese HBV-infected patients were recruited and divided into hepatocellular carcinoma (HCC; n = 94) and non-HCC (n = 272) groups at The First Affiliated Hospital of Sun Yat-Sen University, from April 2009 to December 2012. In the non-HCC group, the patients were classified into three clinical subsets, 76 patients had chronic hepatitis B, 101 were HBV carriers and 95 patients had HBV-related cirrhosis. Two hundred eight unrelated healthy controls were also included. Genomic DNA was extracted from peripheral blood. Single nucleotide polymorphisms (SNPs) rs13143866, rs2221903, and rs907715 were subsequently genotyped using the SNaPshot SNP technique.There were no significant differences in allele and genotype frequencies of SNPs rs13143866, rs2221903, and rs907715 between chronic HBV-infected patients and control subjects. Furthermore, no significant differences were found in the frequencies of all alleles and genotypes between the HCC group and the non-HCC group. However, in the subgroup analysis, IL21 rs13143866 genotype AA frequency in the HBV carrier group was higher than in controls (OR = 6.280, 95%CI: 1.238-31.854; P = 0.019), and the effect of the recessive model (AA vs GG + GA, OR = 6.505, 95%CI: 1.289-32.828) was observed in the HBV carrier group. IL21 rs2221903 genotype TC frequency in the HBV carrier group was higher than in controls (OR = 1.809, 95%CI: 1.043-3.139; P = 0.035). In the haplotype analysis, the ATA haplotype (rs13143866, rs2221903, and rs907715) of IL21 was more frequent in the HCC group than in the non-HCC group (0.165 vs 0.104, P = 0.044; OR = 1.700, 95%CI: 1.010-2.863).Genotypes rs13143866 AA and rs2221903 TC are risk factors for carrying HBV; ATA haplotype increases the risk of HBV-related HCC onset in a Chinese population.
Project description:BACKGROUND AND AIMS:There is lack of a practical biomarker to predict sustained virological response (SVR) in chronic hepatitis B (CHB) patients undergoing peginterferon alfa-2a (PEG-IFN). The aim of this pilot study was to identify immunological features associated with SVR. METHODS:Consecutive 74 CHB patients receiving 24 weeks (for hepatitis B e antigen (HBeAg)-positive) or 48 weeks (for HBeAg-negative) PEG-IFN, were prospectively enrolled. Serum HBV viral loads, hepatitis B surface antigen (HBsAg), CXCL9, IFN-?-inducible protein 10 (IP-10), interferon-gamma (IFN-?) and transforming growth factor beta (TGF-?) were measured at baseline and week 12. SVR was defined as HBeAg seroconversion combined with viral load <2000 IU/mL in HBeAg-positive (n=36), and viral load <2000 IU/mL in HBeAg-negative patients (n=38) at 48 weeks after the end of treatment. RESULTS:Nineteen patients (25.7%), 7 in HBeAg-positive and 12 in HBeAg-negative, achieved SVR. There were significant declines of HBV DNA, HBsAg, IP-10 and IFN-? levels at week 12. In multivariate analysis, pre-treatment CXCL9 >80 pg/mL, HBV DNA <2.5 x 10(7) IU/mL and on-treatment HBV viral load, HBsAg decline >10% at week 12 were predictors of SVR. The performance of CXCL9 in predicting SVR was good in patients with HBV DNA <2.5 x 10(7) IU/mL, particularly in HBeAg-negative CHB cases (positive predictive value, PPV= 64.3%). CONCLUSIONS:Pre-treatment CXCL9 level has the potential to select CHB patients who can respond to PEG-IFN, especially in HBeAg-negative patients with low viral loads.
Project description:Interleukin-21 (IL-21) is a pleiotropic cytokine linking innate and adaptive immune responses, which has been reported to play a key role in multiple autoimmune diseases. The aim of the present case-control study was to investigate the genetic association between single nucleotide polymorphisms (SNPs) of rs907715 within the IL-21 gene and Graves' disease (GD) in a Southern Chinese population. A total of 211 patients with GD and 212 control subjects were recruited for the study. IL-21 gene rs907715 polymorphisms were detected by direct DNA sequencing. The results indicated that the frequencies of the GG genotype and the G allele in GD patients were significantly increased when compared with the frequencies in the controls (P=6.7×10-3 and P=2.0×10-5, respectively). In addition, the frequency of the AA genotype was much lower in the patient group when compared with the control group (16.6 vs. 34.0%; P=4.0×10-5). Furthermore, the G allele of rs907715 was associated with relapse in GD patients. These observations indicated that polymorphisms of IL-21/rs907715 may affect the susceptibility to GD in a Southern Chinese population. The G allele was significantly associated with an increased risk of GD development, whereas the A allele may lower the susceptibility to GD.
Project description:BACKGROUND:(Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. METHODS:In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. RESULTS:Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFN? and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. CONCLUSIONS:Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. CLINICAL TRIALS REGISTATION:NCT01401400.
Project description:Background/Aims:The optimal duration of nucleos(t)ide analogs (NAs) therapy in chronic hepatitis B (CHB) patients remains unsatisfactory. Previous studies have confirmed the important role of host genetic factors in determining the outcome of HBV infection. This study tries to determine the role of host genetic factors in predicting response status in CHB patients discontinuing NAs according to stringent cessation criteria. Patients and Methods:Participating patients came from a prospective NAs- discontinuation cohort since June 1999. Six single-nucleotide polymorphisms (SNPs) were selected according to previous report. SNaPshot assay was used for DNA SNPs analyses. Results:Seventy-six CHB patients were enrolled in our study, of which 61 patients were HBeAg-positive and 15 patients were HBeAg-negative. rs1883832 in the Kozak sequence of CD40 displayed an AUROC of 0.778 in predicting response status in CHB patients with HBeAg seroconversion and a genotype of CT was associated with sustained response in this subpopulation. The diagnostic performance of combinative index (rs1883832, age, and HBsAg at discontinuation) seemed to be better than that of rs1883832, but no statistical difference was observed. rs1883832 was also evaluated as an independent factor for response status by multivariate logistic regression. For HBeAg-negative CHB patients, rs9277535 at HLA-DP presents a Spearman correlation coefficient of 0.582 (P = 0.023) with virological relapse after discontinuation of NAs. Conclusions:rs1883832 serves as a valuable predictive factor for CHB patients with HBeAg seroconversion. rs9277535 at HLA-DP might also be a valuable predictive factor for CHB patients with HBeAg-negative, however, further verifications are recommended due to study limitations.
Project description:The 2 reported trials investigated the effectiveness of treatment with peginterferon alfa-2a in Asian patients with chronic hepatitis B (CHB).Patients with HBeAg-positive (n = 708) or HBeAg-negative (n = 332) CHB were enrolled in 2 randomized, double blind, placebo-controlled studies. Patients received peginterferon alfa-2a 180 mug once weekly, peginterferon plus lamivudine 100 mg per day, or lamivudine alone for 48 weeks. Patients were followed up at 6 and 12 months posttreatment.Peginterferon alfa-2a provided significantly higher rates of HBeAg seroconversion (31%) in HBeAg-positive patients than did lamivudine (19%, P = 0.005) 6 months posttreatment, irrespective of genotype. Of these, 83% achieving seroconversion during treatment or early posttreatment sustained their response at 12 months posttreatment. In patients who seroconverted, 69% maintained HBV DNA suppression at <10,000 copies/ml and alanine aminotrasferase (ALT) normalization. In HBeAg-negative patients, peginterferon produced a significantly higher combined response of HBV DNA at <20,000 copies/ml and ALT normalization (45%) than lamivudine (31%, P = 0.032), irrespective of genotype. Almost 80% of these patients sustained their response at 12 months posttreatment.In conclusion, a finite course of peginterferon alfa-2a provides significant and sustained treatment benefit in Asian CHB patients, who have traditionally been regarded as difficult to treat.