BackgroundGenome-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 FindingsWe 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).ConclusionThese findings provided convincing evidence that rs9275572 significantly associated with HBV-related HCC.

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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: p trend 5 0.008 in Youan_Beijing samples, p trend 5 0.01 in Guangxi samples, p trend 5 0.01 in Jiangsu samples. rs1570360: p trend 5 0.00003 in Youan_Beijing samples, p trend 5 0.006 in Guangxi samples, p trend 5 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.Hepatocellular carcinoma (HCC) ranks fifth in men and eighth in women among causes of cancer mortality worldwide. It is estimated that about 564,000 new cases of HCC are reported throughout the world each year.1 The geographic areas at highest risk of HCC are located in Eastern Asia, e.g., China. 1,2 The cause of HCC is a complex interplay between multiple factors.3 In China, hepatitis B virus (HBV) infection is the most frequent cause of HCC.

Accumulated evidences indicate that single nucleotide polymorphisms (SNP) are associated with risk of hepatocellular carcinoma (HCC). Activating transcription factor 6 (ATF6) is an important modulator of the unfolded protein response (UPR), which is regarded to be involved in carcinogenesis. So we speculate that SNPs in ATF6 may be associated with susceptibility to HCC. We carried out a two-stage association study in three independent case-control groups in a total of 1,082 chronic hepatitis B (CHB) patients and 816 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 in ATF6 gene were genotyped using TaqMan methods. Functional analyses were conducted to verify the biological significances of the associated SNP. We identified a missense SNP (rs2070150) was significantly associated with susceptibility to HCC (p 5 0.008, 0.001 and 0.007 in Beijing_302, Beijing_You'an and Guangxi samples, respectively). This SNP was further validated in four independent groups of major HBV outcomes, indicating it may associate exclusively to HCC. ATF6 mRNA expression was significantly decreased as the disease progressed (p <0.001). Functional analyses show that the protective allele of rs2070150 could significantly increase the expression levels of ATF6 mRNA, as well as ATF6 regulated genes such as GRP78, XBP1 and CHOP. These findings indicate that a common missense SNP in ATF6 may contribute to susceptibility of HCC functionally.Hepatocellular carcinoma (HCC) is common cancer mortality worldwide. It is estimated that there are about 564,000 new cases of HCC each year throughout the world.1 The geographic areas with higher morbidity of HCC are located in Eastern Asia such as China. 1,2 The cause of HCC is a complex interplay between multiple factors of host genetic and

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.

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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.

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