Leukocyte Telomere Length-Related rs621559 and rs398652 Genetic Variants Influence Risk of HBV-Related Hepatocellular Carcinoma

PLOS ONE, Dec 2019

Recent genome-wide association studies (GWAS) have identified eleven leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Since LTL has been associated with risk of many malignancies, LTL-related SNPs may contribute to cancer susceptibility. To test this hypothesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we genotyped these eleven LTL-related SNPs in a case-control set including 1186 HBV-related HCC cases, 508 chronic HBV carriers and 1308 healthy controls at the discovery stage. The associations of HCC risk with these SNPs were further confirmed in an independent case-control set. We found that 1p34.2 rs621559 and 14q21 rs398652 were significantly associated with HBV-related HCC risk (both P<0.005 after Bonferroni corrections). There was no significant difference of either rs621559 or rs398652 genotypes between chronic HBV carriers and healthy controls, demonstrating that the association was not due to predisposition to HBV infection. In the pooled analyses (1806 HBV-related HCC cases and 1954 controls), we observed a decreased HCC risk, 0.72-times, associated with the 1p34.2 rs621559 AA genotype compared to the GG genotype (P = 1.6×10−6). Additionally, there was an increased HCC risk, 1.27-fold, associated with the rs398652 GG genotype (P = 3.3×10−6). A statistical joint effect between the rs621559 GG and rs398652 GG genotypes may exist in elevating risk of HBV-related HCC. We show, for the first time, that rs398652 and rs621559 might be marker genetic variants for risk of HBV-related HCC in the Chinese population.

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Leukocyte Telomere Length-Related rs621559 and rs398652 Genetic Variants Influence Risk of HBV-Related Hepatocellular Carcinoma

et al. (2014) Leukocyte Telomere Length-Related rs621559 and rs398652 Genetic Variants Influence Risk of HBV- Related Hepatocellular Carcinoma. PLoS ONE 9(11): e110863. doi:10.1371/journal.pone.0110863 Leukocyte Telomere Length-Related rs621559 and rs398652 Genetic Variants Influence Risk of HBV-Related Hepatocellular Carcinoma Wenting Pan 0 Guangxia Cheng 0 Huaixin Xing 0 Juan Shi 0 Chao Lu 0 Jinyu Wei 0 Lichao Li 0 Changchun Zhou 0 Qipeng Yuan 0 Liqing Zhou 0 Ming Yang 0 Amanda Ewart Toland, Ohio State University Medical Center, United States of America 0 1 State Key Laboratory of Chemical Resource Engineering, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology , Beijing , China , 2 Clinical Laboratory, Jinan Infectious Disease Hospital, Shandong University , Jinan, Shandong Province , China , 3 Department of Anesthesiology, Shandong Cancer Hospital, Shandong Academy of Medical Sciences , Jinan, Shandong Province , China , 4 Clinical Laboratory, Shandong Cancer Hospital, Shandong Academy of Medical Sciences , Jinan, Shandong Province , China , 5 Department of Radiation Oncology, Huaian No. 2 Hospital , Huaian, Jiangsu Province , China Recent genome-wide association studies (GWAS) have identified eleven leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Since LTL has been associated with risk of many malignancies, LTL-related SNPs may contribute to cancer susceptibility. To test this hypothesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we genotyped these eleven LTL-related SNPs in a case-control set including 1186 HBV-related HCC cases, 508 chronic HBV carriers and 1308 healthy controls at the discovery stage. The associations of HCC risk with these SNPs were further confirmed in an independent case-control set. We found that 1p34.2 rs621559 and 14q21 rs398652 were significantly associated with HBV-related HCC risk (both P,0.005 after Bonferroni corrections). There was no significant difference of either rs621559 or rs398652 genotypes between chronic HBV carriers and healthy controls, demonstrating that the association was not due to predisposition to HBV infection. In the pooled analyses (1806 HBV-related HCC cases and 1954 controls), we observed a decreased HCC risk, 0.72-times, associated with the 1p34.2 rs621559 AA genotype compared to the GG genotype (P = 1.661026). Additionally, there was an increased HCC risk, 1.27-fold, associated with the rs398652 GG genotype (P = 3.361026). A statistical joint effect between the rs621559 GG and rs398652 GG genotypes may exist in elevating risk of HBV-related HCC. We show, for the first time, that rs398652 and rs621559 might be marker genetic variants for risk of HBV-related HCC in the Chinese population. - . These authors contributed equally to this work. Introduction Human telomeres, consisting of TTAGGG short repetitive sequences, locate at the ends of chromosomes [1,2]. The core function of telomeres is to protect chromosomes integrity, prevent chromosomal instability, and avoid the activation of DNA-damage responses [1,2]. Because of the end replication problem, telomeres would shorten after each DNA replication and each cell division in normal cells. When telomeres shrink to be tremendously short, these normal cells would go through cellcycle arrest, apoptosis or senescence [1]. Nevertheless, in cancer cells, telomerase can synthesize telomere repeats de novo and overcome telomere attrition [14]. Therefore, malignant cells with over-expressed telomerase can unlimitedly grow in vitro and in vivo [1]. However, in normal human leukocytes without or with little telomerase activity, telomere length shortens with age at a rate of 20,40 base pairs (bp) per year [5,6]. Leukocyte telomere length (LTL) has been associated with risk to developing many malignancies [718], highlighting the predictive role of LTL in carcinogenesis. It has been reported that LTL is genetically heritable, with heritability ranging from 44% to 80% [1921]. Recently, several genome-wide association studies (GWAS) identified eleven single nucleotide polymorphisms (SNPs) which are associated with LTL in different ethnic populations [9,2225]. For example, Gu J et al. found that four SNPs (rs398652 on 14q21, rs621559 on 1p34.2, rs6028466 on 20q11.22 and rs654128 on 6q22.1) were associated with LTL in Caucasian populations (pooled P,1025). In a large casecontrol study, they observed that subjects with the variant allele of rs398652 has a significantly reduced risk of bladder cancer [Odds ratio (OR) = 0.81; 95% Confidence interval (CI) = 0.67 0.97; P = 0.025], consistent with the correlation of this variant allele with longer telomeres. In a previous study, we also investigated whether these four genetic variants are associated with LTL and risk of esophageal squamous cell carcinoma (ESCC) in Chinese populations [26]. After measuring LTL of 550 healthy individuals, (...truncated)


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Wenting Pan, Guangxia Cheng, Huaixin Xing, Juan Shi, Chao Lu, Jinyu Wei, Lichao Li, Changchun Zhou, Qipeng Yuan, Liqing Zhou, Ming Yang. Leukocyte Telomere Length-Related rs621559 and rs398652 Genetic Variants Influence Risk of HBV-Related Hepatocellular Carcinoma, PLOS ONE, 2014, Volume 9, Issue 11, DOI: 10.1371/journal.pone.0110863