Regulatory polymorphisms in the promoter of CXCL10 gene and disease progression in male hepatitis B virus carriers.
OBJECTIVE
The importance of expression of interferon gamma-inducible protein of 10 kilodaltons (IP-10, CXCL10) during chronic hepatitis B virus (HBV) infection has been recently emphasized. In this report, we investigated whether the naturally occurred sequence variations in the CXCL10 gene impact liver damage and disease progression of chronic HBV infection.


METHODS
A hospital-based case-control study was conducted, and a total of 613 and 1787 unrelated Han Chinese HBV carriers were recruited from Beijing and Chongqing, respectively. We systematically screened sequence variations in the CXCL10 gene and examined the association between the variations in this gene and susceptibility to disease progression of chronic HBV infection in Chinese populations from Beijing and Chongqing. Functional analyses were conducted to verify the biological significances of the associated genetic variation.


RESULTS
We identified that the polymorphism G-201A, located in the promoter region of CXCL10, was associated with susceptibility to disease progression in male HBV carriers (dominant model; odds ratio, 1.53; P = .001). Functional analyses show that the G-201A polymorphism alters the binding affinity of nuclear protein and regulates CXCL10 expression. We observed higher CXCL10 transcription in interferon gamma-stimulated peripheral blood mononuclear cells with the disease-susceptible genotypes. Enzyme-linked immunosorbent assay and immunohistochemical analysis showed augmented CXCL10 production in serum and liver tissues of progressed HBV carriers.


CONCLUSIONS
The novel regulatory polymorphism G-201A [corrected] in the promoter of CXCL10 gene could be a part of the genetic variation underlying the susceptibility of individuals to disease progression of chronic HBV infection.
Deng
Guohong
G
Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.
Zhou
Gangqiao
G
Zhang
Rong
R
Zhai
Yun
Y
Zhao
Wenli
W
Yan
Zehui
Z
Deng
Chunqing
C
Yuan
Xiaoyan
X
Xu
Baoyan
B
Dong
Xiaojia
X
Zhang
Xiumei
X
Zhang
Xuqing
X
Yao
Zhijian
Z
Shen
Yan
Y
Qiang
Boqing
B
Wang
Yuming
Y
He
Fuchu
F
D000328:Adult; D044466:Asian People / Q000235:genetics; D002353:Carrier State; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D002681:China; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D019694:Hepatitis B, Chronic / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008099:Liver / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018570:Risk Assessment; D012307:Risk Factors; D014158:Transcription, Genetic; D014162:Transfection
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007371:Interferon-gamma