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

Authors

  • Xiaopan Wu,

    1. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China
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  • Zhenhui Xin,

    1. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China
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  • Wei Zhang,

    1. Beijing Center for Disease Control and Prevention, Beijing, People's Republic of China
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  • Jia Wu,

    1. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China
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  • Kangmei Chen,

    1. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China
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  • Huifen Wang,

    1. Liver Failure Treatment and Research Center, the 302 Hospital of the PLA, Beijing, People's Republic of China
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  • Xilin Zhu,

    1. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China
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  • Liping Pan,

    1. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China
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  • Zhuo Li,

    1. Department of Infectious Disease, Affiliated Youan Hospital, Capital University of Medical Science, Beijing, People's Republic of China
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  • Hui Li,

    Corresponding author
    1. School of Basic Medicine, Peking Union Medical College, Beijing
    • Department of Epidemiology, Institute of Basic Medical Sciences, Beijing, People's Republic of China
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  • Ying Liu

    Corresponding author
    • National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, People's Republic of China
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Correspondence to: Ying Liu, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, 5 Dongdan 3 Tiao, Beijing 100005, People's Republic of China, Tel.: +86-10-65296419; Fax: +86-10-65296419, E-mail: liuyingpumc@yahoo.com Hui Li, Department of Epidemiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, 5 Dongdan 3 Tiao, Beijing 100005, People's Republic of China, E-mail: lihui99360@sohu.com

Abstract

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.

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