Zhenhui Xin

Evaluation of susceptibility locus for response to interferon-α based therapy in chronic hepatitis B patients in Chinese.

In 2009, three independent genome-wide association studies reported that genetic variation in the interleukin 28B gene to be associated with the response to interferon-α/ribavirin therapy in hepatitis C virus genotype 1 infected patients. We carried out the present study to assess whether such polymorphisms also affect the therapy effect of another interferon-α responsive illness as chronic hepatitis B. Five hundred and twelve interferon-α treatment-naïve HBeAg seropositive chronic hepatitis B patients were enrolled in the present retrospective nested case-control study. All patients received PEG-IFN-α-2a based treatment and were examined for the therapy efficacy. SNP rs8099917 was genotyped using the MassArray system (Sequenom). Interestingly, the frequency of G allele of rs8099917 was significantly higher in response group than in non response group (8.3% vs. 3.9%, p=0.003, OR=0.44, 95%CI=0.25-0.79). The genotype distributions of this SNP also differed significantly between two groups (p=0.003). Our study suggested that the G allele of rs8099917 was associated with higher rate of response in HBeAg seropositive chronic hepatitis B patients treated with interferon α.

Replication of Genome Wide Association Studies on Hepatocellular Carcinoma Susceptibility Loci in a Chinese Population

Background Genome-wide association studies (GWAS) have identified three loci (rs17401966 in KIF1B, rs7574865 in STAT4, rs9275319 in HLA-DQ) as being associated with hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) in a Chinese population, two loci (rs2596542 in MICA, rs9275572 located between HLA-DQA and HLA-DQB) with hepatitis C virus-related HCC (HCV-related HCC) in a Japanese population. In the present study, we sought to determine whether these SNPs are predictive for HBV-related HCC development in other Chinese population as well. Method and Findings We genotyped 4 SNPs, rs2596542, rs9275572, rs17401966, rs7574865, in 506 HBV-related HCC patients and 772 chronic hepatitis B (CHB) patients in Han Chinese by TaqMan methods. Odds ratio(OR)and 95% confidence interval (CI) were calculated by logistic regression. In our case-control study, significant association between rs9275572 and HCC were observed (P = 0.02, OR = 0.73, 95% CI = 0.56–0.95). In the further haplotype analysis between rs2596542 at 6p21.33 and rs9275572 at 6p21.3, G-A showed a protective effect on HBV-related HCC occurrence (P<0.001, OR = 0.66, 95% CI = 0.52–0.84). Conclusion These findings provided convincing evidence that rs9275572 significantly associated with HBV-related HCC.

Polymorphisms in the VEGFA promoter are associated with susceptibility to hepatocellular carcinoma by altering promoter activity.

Accumulated evidences indicate that single nucleotide polymorphisms (SNP) in angiogenesis and tumorigenesis related genes are associated with risk of hepatocellular carcinoma (HCC). Vascular endothelial growth factor A (VEGFA), one of the most significant mediators of angiogenesis, plays an important role in carcinogenesis and development via promoting tumor growth. We carried out a two‐stage association study in 1,838 chronic hepatitis B (CHB) patients and 1,207 hepatitis B virus (HBV) related HCC patients in Han Chinese populations from Beijing, Guangxi and Jiangsu. We systematically screened polymorphisms in the VEGFA gene and examined the association between the SNPs and susceptibility to HCC. Functional analyses were conducted to verify biological significances of associated SNPs. We identified two promoter SNPs (rs833061 and rs1570360) were associated with susceptibility to HCC (rs833061: ptrend = 0.008 in Youan_Beijing samples, ptrend = 0.01 in Guangxi samples, ptrend = 0.01 in Jiangsu samples. rs1570360: ptrend = 0.00003 in Youan_Beijing samples, ptrend = 0.006 in Guangxi samples, ptrend = 0.02 in Jiangsu samples). These two SNPs were further validated in four independent groups of major HBV outcomes, indicating rs833061 and rs1570360 may associate exclusively to HCC. Functional analyses show that CA haplotype constructed by rs833061 and rs1570360 had higher luciferase activity compared with TG haplotype (p < 0.05). A 18 bp insert/del polymorphism was in absolute linkage disequilibrium (LD) with rs833061. The 18 bp insert allele created a Sp1 binding site. We observed higher VEGFA transcription in peripheral blood of HCC patients compared with CHB patients and healthy individuals (p < 0.05). These findings indicate that VEGFA promoter SNPs may contribute to susceptibility of HCC by altering promoter activity.

Polymorphisms in the potential functional regions of the TGF‐β 1 and TGF‐β receptor genes and disease susceptibility in HBV‐related hepatocellular carcinoma patients

Hepatocellular carcinoma (HCC) is a disease of multiple etiologies caused by the accumulation of genetic and epigenetic defects. Current evidence indicates that the transforming growth factor beta (TGF‐β) signaling pathway has a significant impact on different cellular process. Members of the TGF‐β superfamily (TGF‐β1, the type I TGF‐β receptor [TβRI], type II TGF‐β receptor [TβRII], and type III TGF‐β receptor]) play an important role in tumorigenesis. Numerous studies show that genetic polymorphisms in TGF‐β superfamily genes are associated with HCC in East Asian populations. We studied 16 single nucleotide polymorphisms (SNPs) in four genes (TGF‐β1, TβRI, TβRII, and TβRIII) to examine their associations with hepatocarcinogenesis. A total of 1228 Chinese Han participants were enrolled in the study (881 control participants who were negative for all hepatitis B virus [HBV] serum markers and 347 case participants with HBV‐related HCC). Genotyping was conducted using the TaqMan method. The results showed that the frequency of the rs1805110 T allele was significantly higher in the case group than in the control group (P = 0.034). After stratification, the results for rs1805110 remained significant in male participants (P = 0.005), but there was no statistical difference in females. In males, the frequency of the C‐C‐G‐C‐A haplotype resulting from SNPs rs1805110, rs2810904, rs1805112, rs284878, and rs1804506 in TβRIII was significantly lower in the case group than in the control group (P = 0.001), whereas the reverse was true for the T‐C‐G‐C‐A haplotype (P = 0.036). We conclude that the rs1805110T allele is associated with susceptibility to HBV‐related HCC in males.

Evaluation of the Association Between the ADRA2A Genetic Polymorphisms and Type 2 Diabetes in a Chinese Han Population

Alpha-2-adrenergic receptor (ADRA2A) is involved in the sympathetic nervous system and plays a role in the regulation of insulin secretion and lipolysis. Recent studies have indicated that the ADRA2A polymorphisms are associated with type 2 diabetes (T2DM) in Caucasians and African Americans. The present study aimed to evaluate the association between the ADRA2A polymorphisms and T2DM in a Chinese Han population. Two single-nucleotide polymorphisms (SNPs) rs521674 and rs553668 in the ADRA2A gene were genotyped in 2094 Chinese subjects (1042 T2DM patients and 1052 nondiabetic controls) by using the TaqMan allelic discrimination technique. A single-locus analysis indicated that SNP rs553668 was associated with T2DM (p=0.04). Further analysis indicated that the association of SNP rs553668 was found in T2DM patients with body mass index (BMI)<25 kg/m(2) (p=0.03), but not in the patients with BMI≥25 kg/m(2) (p=0.56). This association was still significant in a recessive model (p=0.01, odds ratio=0.68, 95% confidence interval=0.51-0.92). In conclusion, the present study provides evidence that the ADRA2A polymorphism, rs553668, is associated with lean T2DM patients in a Chinese Han population. Further investigation to explore the role of ADRA2A in the regulation of body weight has been taken into our consideration.

Association of Polymorphisms in Mitofusin-2 Gene with Type 2 Diabetes in Han Chinese

MFN2 and ESRRA are candidate genes involved in the pathogenesis of T2D. Five tag-SNPs in MFN2 gene and three in ESRRA gene were selected and genotyped with TaqMan or PCR-RFLP method in stage 1 populations (555 patients with T2D and 649 control subjects) and stage 2 populations (546 patients with T2D versus 419 control subjects) in Han Chinese. And combining our published data, we estimated the interactions between genetic variants in the MFN2, ESRRA, and PGC-1α genes on the T2D risk using MDR. rs873458 (G > A) and rs2878677 (C > T) in MFN2 gene were significantly associated with T2D (P = 0.005 and 0.01) in stage 1 populations, and the association of other SNPs with T2D was not found. In stage 2 populations, we further confirmed the association between rs2878677 and T2D (P = 0.01). Combining the two stage populations, the data supported more significant effect of rs873458 and rs2878677 on T2D risk (P = 0.003 and 0.0001). A-C-G-T-C and G-T-C-T-C in MFN2 had significant association with T2D (P = 0.007 and 0.009). The present study also provided the evidence that MFN2 had interactions with PGC-1α (P < 0.0001) or ESRRA (P < 0.0001). This study suggested a role of MFN2 polymorphism in the risk of T2D; however, further studies are needed.

Polymorphisms in ADAR1 gene affect response to interferon alpha based therapy for chronic hepatitis B in Han Chinese

Host genetic polymorphisms in interferon pathway genes are reported to be associated with response to interferon therapy. Five hundred and forty-eight α interferon treatment-naïve chronic hepatitis B patients were enrolled in the retrospective nested case-control study. All patients received α interferon based treatment and were examined for therapy efficacy. We genotyped 115 polymorphisms from 16 interferon pathway genes using the MassArray system. We identified rs4845384 in ADAR1 gene is strongly associated with the outcome of interferon therapy allele dose-depended (P=0.0005), with decreased odds ratios of 0.69 and 0.27 for GA and AA genotypes, respectively (95% confidence interval, 0.47-0.99 for GA; 0.11-0.64 for AA). Our study suggested that rs4845384 in ADAR1 associates with treatment-induced clearance of chronic hepatitis B.

Human leukocyte antigen class I and class II genes polymorphisms might be associated with interferon α therapy efficiency of chronic hepatitis B

Certain host genetic polymorphisms in human leukocyte antigen (HLA) genes are reported to be associated with response to interferon α (IFNα) therapy. Two hundred and eighteen IFNα treatment-naïve chronic hepatitis B (CHB) patients were enrolled in the present study. HLA-A, B, C and DQA1, DQB1, DRB1 gene alleles were detected by polymerase chain reaction-sequencing based typing (PCR-SBT) and PCR-sequence specific primer (PCR-SSP), respectively. Frequencies of HLA-DQB1*0303 and DRB1*08 in response group were clearly lower than those in nonresponse group (P=0.019, OR=1.81, 95%CI=1.07-3.15; P=0.031, OR=2.43, 95%CI=1.02-5.98, respectively). Frequencies of haplotype *1101-*4601-*0102 (HLA-A, B, C) and haplotype *0302-*0303-*09 (HLA-DQA1, DQB1, DRB1) were clearly lower than those in nonresponse group (P=0.009, OR=4.84, 95%CI=1.29-19.48; P=0.031, OR=1.94, 95%CI=1.01-3.73, respectively). These results suggest that patients with HLA-DQB1*0303 or DRB1*08 alleles, and haplotype *1101-*4601-*0102 (HLA-A, B, C) or haplotype *0302-*0303-*09 (HLA-DQA1, DQB1, DRB1), might be less responsive to IFNα treatment.

A 3′ UTR SNP in COL18A1 Is Associated with Susceptibility to HBV Related Hepatocellular Carcinoma in Chinese: Three Independent Case-Control Studies

Background Accumulated evidences indicate that single nucleotide polymorphisms (SNP) in angiogenesis and tumorigenesis related genes are associated with risk of Hepatocellular carcinoma (HCC). COL18A1 encodes the precursor of endostatin, which is a broad-spectrum angiogenesis inhibitor, and we speculate that SNPs in COL18A1 may be associated with susceptibility to HCC. Methods and Findings We carried out a 2-stage association study in 3 independent case-control groups in a total of 1067 chronic hepatitis B (CHB) patients and 808 hepatitis B virus (HBV) related HCC patients in Han Chinese. Four SNPs which can represent all potential functional SNPs with MAF>0.1 recorded in HapMap database were genotyped using TaqMan methods. Levels of total COL18A1 mRNA were also examined using quantitative real-time RT-PCR. We found that rs7499 located in 3′-UTR to be strongly associated with HBV related HCC (Pcombined = 0.0000005, OR = 0.72, 95%CI = 0.63–0.82). COL18A1 mRNA expression was significantly decreased as the disease progressed (P = 0.000026). Conclusion These findings indicate that COL18A1 rs7499 may contribute to the risk of HCC in Han Chinese.

HBV suppresses thapsigargin‑induced apoptosis via inhibiting CHOP expression in hepatocellular carcinoma cells

[This corrects the article DOI: 10.3892/ol.2017.6666.].