GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers.
Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV-related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV-positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10⁻¹⁹) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10⁻⁸), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10⁻⁴; rs455804: OR = 0.84, P = 6.92×10⁻³). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV-related HCC, suggesting the involvement of glutamate signaling in the development of HBV-related HCC.
Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Shengping
S
Li
Ji
J
Qian
Yuan
Y
Yang
Wanting
W
Zhao
Juncheng
J
Dai
Jin-Xin
JX
Bei
Jia Nee
JN
Foo
Paul J
PJ
McLaren
Zhiqiang
Z
Li
Jingmin
J
Yang
Feng
F
Shen
Li
L
Liu
Jiamei
J
Yang
Shuhong
S
Li
Shandong
S
Pan
Yi
Y
Wang
Wenjin
W
Li
Xiangjun
X
Zhai
Boping
B
Zhou
Lehua
L
Shi
Xinchun
X
Chen
Minjie
M
Chu
Yiqun
Y
Yan
Jun
J
Wang
Shuqun
S
Cheng
Jiawei
J
Shen
Weihua
W
Jia
Jibin
J
Liu
Jiahe
J
Yang
Zujia
Z
Wen
Aijun
A
Li
Ying
Y
Zhang
Guoliang
G
Zhang
Xianrong
X
Luo
Hongbo
H
Qin
Minshan
M
Chen
Hua
H
Wang
Li
L
Jin
Dongxin
D
Lin
Hongbing
H
Shen
Lin
L
He
Paul I W
PI
de Bakker
Hongyang
H
Wang
Yi-Xin
YX
Zeng
Mengchao
M
Wu
Zhibin
Z
Hu
Yongyong
Y
Shi
Jianjun
J
Liu
Weiping
W
Zhou
D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000821:virology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059848:HLA-DQ alpha-Chains / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018092:Kainic Acid Receptors / Q000235:genetics*
D059848:HLA-DQ alpha-Chains; D018092:Kainic Acid Receptors; C069050:HLA-DQA1 antigen