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.
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. 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)