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Polymorphisms in the VEGFA promoter are associated with susceptibility to hepatocellular carcinoma by altering promoter activity
Author(s) -
Wu Xiaopan,
Xin Zhenhui,
Zhang Wei,
Wu Jia,
Chen Kangmei,
Wang Huifen,
Zhu Xilin,
Pan Liping,
Li Zhuo,
Li Hui,
Liu Ying
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28109
Subject(s) - single nucleotide polymorphism , hepatocellular carcinoma , haplotype , carcinogenesis , linkage disequilibrium , angiogenesis , biology , vascular endothelial growth factor a , allele , snp , vascular endothelial growth factor , promoter , cancer research , oncology , genotype , immunology , medicine , genetics , gene , vegf receptors , gene expression
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 = 0.008 in Youan_Beijing samples, p trend = 0.01 in Guangxi samples, p trend = 0.01 in Jiangsu samples. rs1570360: p trend = 0.00003 in Youan_Beijing samples, p trend = 0.006 in Guangxi samples, p trend = 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.