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

Chen, Kangmei; Shi, Weimei; Xin, Zhen-Hui; Wang, Huifen; Zhu, Xilin; Wu, Xiaopan; Li, Zhuo; Li, Hui; Liu, Ying

doi:10.1371/journal.pone.0077315

Cited by 38 publications

(41 citation statements)

References 23 publications

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“…By comparing the HBV carrier and CHB groups, our results were in accordance with the Caucasian study or another study with Chinese populations, where no significant association of SNPs in HLA-DP/DQ with the progression of HBV-related diseases was detected (Vermehren et al 2012;Li et al 2011). There has been controversy regarding the association of the HLA region and the transformation of CHB to HC or HCC according to the reported studies on Chinese populations (Hu et al 2012;Jiang et al 2013;Chen et al 2013) and eastern Asian or Saudi Arab populations (Al-Qahtani et al 2014). Specifically, in this study, we observed no significant association of SNPs in the HLA-DP/DQ region with the progression of CHB to HC.…”

Section: Discussioncontrasting

confidence: 70%

“…Moreover, there exists a significant association of SNPs rs2856718 and rs9275319 in HLA-DQ as well as rs3077 in HLA-DP with the progression of CHB to HCC (Hu et al 2012;Jiang et al 2013;Chen et al 2013). In contrast, no significant association was revealed between SNPs rs3077 and rs9277542 in HLA-DP in a Korean sample and rs2856718, rs7453920 and rs9275572 in HLA-DQ, and rs3077 and rs9277535 in HLA-DP in the Saudi Arabian sample of patients with HC or HCC (Al-Qahtani et al 2014;Nishida et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection

Tao

et al. 2015

Amino Acids

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Recent genome-wide association studies have revealed the HLA region on chromosome 6p21 as a susceptibility locus for hepatitis B virus (HBV) infection, a finding subsequently replicated in independent samples. However, only limited single nucleotide polymorphisms (SNPs) were analyzed in most of these studies, and it remains to be determined which SNPs contribute to the detected association. After genotyping 140 SNPs within this genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls, we conducted a series of genetic epidemiological and bioinformatics analysis, including individual SNP-based association analysis, haplotype-based association analysis, and conditional analysis. We identified 76 SNPs and 5 LD blocks in HLA-DP/DQ clusters that are significantly associated with HBV infection, with the smallest P value being 3.88 × 10(-18) for rs9277535 in HLA-DPB1. With conditional analysis, we further revealed that the genes contributing to the effects of variants in HLA-DP/DQ on infection are independent of each other, and the LD block 5 in the 3'-UTR region of HLA-DPB1 had a predominant effect in the association of HLA-DP with HBV infection. We also found that the SNPs in the 3'-UTR region of HLA-DPB1 were significant between the subgroups of inactive HBV carrier, chronic hepatitis B, or hepatic cirrhosis from the case group and the spontaneous HBV-clearance subgroup from the control group. Finally, we did further association analysis of SNPs in this region with different subgroups from the case group, which revealed no association of these SNPs with the progression of HBV-related diseases. In sum, we showed, for the first time, that the HLA-DP/DQ clusters contribute independently to HBV infection, and the 3'-UTR region of HLA-DPB1 represents an important functional region involved in HBV infection.

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Section: Discussioncontrasting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection

Tao

et al. 2015

Amino Acids

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“…The SNPs rs3077 and rs9277535 of HLA-DP have been reported to be associated with the persistence of HBV infection and with spontaneous HBV clearance (Guo et al, 2011;Cheng et al, 2013;Hu et al, 2013). Recently, a relationship between the HLA-DP gene and HCC susceptibility has been reported by multiple labs, but the results have been discordant Li et al, 2011;Hu et al, 2012;Chen et al, 2013;Al-Qahtani et al, 2014;Posuwan et al, 2014). Therefore, in order to clarify the role of HLA-DP polymorphisms in HCC susceptibility, a systematic review and meta-analysis of published data were carried out in this study.…”

Section: Introductionmentioning

confidence: 99%

Relationship between HLA-DP gene polymorphisms and the risk of hepatocellular carcinoma: a meta-analysis

Zhang

Zheng

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The association between the HLA-DP single nucleotide polymorphisms (SNPs) rs3077 and rs9277535 and hepatocellular carcinoma (HCC) has been reported, but results have been inconclusive and controversial. Therefore, to investigate the relationship between these HLA-DP SNPs and HCC susceptibility, a meta-analysis of studies published before January 2014 was carried out using the PubMed and Google Scholar databases. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated for HLA-DP alleles, and for co-dominant, dominant, and recessive genotype models of each SNP, based on fixed-or randomeffects models. A total of nine studies from six published articles were included. The association study between rs3077 and HCC susceptibility was performed in four independent comparisons that contained 1871 cases with hepatitis B virus (HBV)-related HCC and 3207 carriers with (2015) persistent HBV. Association between rs9277535 and HCC susceptibility was examined in five separate comparisons that contained 2017 cases and 3930 carriers. Our analysis indicated a significant association of rs3077 and rs9277535 with HCC susceptibility, suggesting that rs3077 might act beneficially against HCC susceptibility (A vs G: OR = 0.884, 95%CI = 0.803-0.973, P = 0.012; GA vs GG: OR = 0.842, 95%CI = 0.733-0.967, P = 0.015; AA+GA vs GG: OR = 0.848, 95%CI = 0.744-0.968, P = 0.014), and that rs9277535 might promote HCC susceptibility (AA vs GA: OR = 1.202, 95%CI = 1.011-1.428, P = 0.037). This study suggested that HLA-DP rs3077 and rs9277535 polymorphisms are associated with HCC susceptibility in the Asian population.

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“…The association of MICA-129 with psoriasis (32) has been disproven in large GWAS cohorts (71). However, associations with NPC (33) and HCC (34) are supported by GWAS data pointing to the MICA gene region (44–46). …”

Section: Mica-129met/val Disease Associations In View Of Biological Fmentioning

confidence: 98%

“…However, since the MICA-129Met/Val dimorphism is functional, it could also indicate that we need to better understand this function to predict its consequences in the pathophysiology of different diseases in various populations, which might be exposed to different interfering environmental factors. This assumption is supported by genome-wide association studies (GWAS), which have assigned disease risks for NPC (44), HCC (45, 46), cervical cancer (47, 48), and asthma (49) or advantages, such as HIV long-term non-progression (50) to the MICA gene region in an unbiased manner.…”

Section: Mica-129met/val Disease Association Studiesmentioning

confidence: 99%

Impact of the MICA-129Met/Val Dimorphism on NKG2D-Mediated Biological Functions and Disease Risks

et al. 2016

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The major histocompatibility complex (MHC) class I chain-related A (MICA) is the most polymorphic non-classical MHC class I gene in humans. It encodes a ligand for NKG2D (NK group 2, member D), an activating natural killer (NK) receptor that is expressed mainly on NK cells and CD8+ T cells. The single-nucleotide polymorphism (SNP) rs1051792 causing a valine (Val) to methionine (Met) exchange at position 129 of the MICA protein is of specific interest. It separates MICA into isoforms that bind NKG2D with high (Met) and low affinities (Val). Therefore, this SNP has been investigated for associations with infections, autoimmune diseases, and cancer. Here, we systematically review these studies and analyze them in view of new data on the functional consequences of this polymorphism. It has been shown recently that the MICA-129Met variant elicits a stronger NKG2D signaling, resulting in more degranulation and IFN-γ production in NK cells and in a faster costimulation of CD8+ T cells than the MICA-129Val variant. However, the MICA-129Met isoform also downregulates NKG2D more efficiently than the MICA-129Val isoform. This downregulation impairs NKG2D-mediated functions at high expression intensities of the MICA-Met variant. These features of the MICA-129Met/Val dimorphism need to be considered when interpreting disease association studies. Particularly, in the field of hematopoietic stem cell transplantation, they help to explain the associations of the SNP with outcome including graft-versus-host disease and relapse of malignancy. Implications for future disease association studies of the MICA-129Met/Val dimorphism are discussed.

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

Cited by 38 publications

References 23 publications

Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection

Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection

Relationship between HLA-DP gene polymorphisms and the risk of hepatocellular carcinoma: a meta-analysis

Impact of the MICA-129Met/Val Dimorphism on NKG2D-Mediated Biological Functions and Disease Risks

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