Regulatory Polymorphisms in the Promoter of CXCL10 Gene and Disease Progression in Male Hepatitis B

[Guest guest]

Clinical–Liver, Pancreas, and Biliary Tract

Regulatory Polymorphisms in the Promoter of CXCL10 Gene and Disease Progression

in Male Hepatitis B Virus rs

Guohong Deng‡, Gangqiao Zhou, §, Rong Zhang, Yun Zhai, §, Wenli Zhao‡, Zehui

Yan‡, Chunqing Deng‡, Xiaoyan Yuan, Baoyan Xu‡, Xiaojia Dong§, Xiumei Zhang,

Xuqing Zhang‡, Zhijian Yao§, Yan Shen§, Boqing Qiang§, Yuming Wang‡, , and

Fuchu He, §, ¶, ,

‡Department of Infectious Diseases, Southwest Hospital, Third Military Medical

University, Chongqing, China

State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing

Institute of Radiation Medicine, Beijing, China

Institute of Pathology, Southwest Hospital, Third Military Medical University,

Chongqing, China

§Chinese National Human Genome Center at Beijing, Beijing, China

¶Institute of Biomedical Sciences, Fudan University, Shanghai, China

Received 14 August 2007; accepted 13 December 2007. Available online 1 January

2008.

Background & Aims: 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-210A 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.

Abbreviations: ANOVA, analysis of variance; ChIP, chromatin immunoprecipitation;

CI, confidence interval; htSNP, haplotype-tagged single nucleotide polymorphism;

IFN, interferon; LD, linkage disequilibrium; OR, odds ratio; PCR, polymerase

chain reaction; SNP, single nucleotide polymorphism

G.D. and G.Z. contributed equally to this work. The Department of Infectious

Diseases, Southwest Hospital, and the State Key Laboratory of Proteomics,

Beijing Proteome Research Center contributed equally to this work.

Supported in part by grants from the Chinese High-tech Program (2006AA02A412),

Chinese National Natural Science Fund for Creative Research Groups Program

(30621063), Chinese National Basic Research Program (2006CB910803 and

2007CB512903), Beijing Science & Technology NOVA Program (2006A54), and Chinese

National Natural Science Foundation (30470964 and 30671850).

The authors report they have no conflicts of interest to disclose. The funding

sources had no role in study design, collection, analysis, or interpretation of

data; the writing of the report; or the decision to submit the report for

publication.

Address requests for reprints to: Fuchu He, PhD, State Key Laboratory of

Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation

Medicine, Beijing, 100850, P. R. China. fax: (86) 10-68177417

Yuming Wang, Department of Infectious Diseases, Southwest Hospital, Third

Military Medical University, Chongqing, 400038, P. R. China. fax: (86)

23-65334998.

Gastroenterology

Volume 134, Issue 3, March 2008, Pages 716-726.e2

http://www.sciencedirect.com/science?_ob=ArticleURL & _udi=B6WFX-4RGM0RK-1 & _user=1\

0 & _coverDate=03%2F31%2F2008 & _rdoc=19 & _fmt=summary & _orig=browse & _srch=doc-info(%2\

3toc%236806%232008%23998659996%23682098%23FLA%23display%23Volume) & _cdi=6806 & _sor\

t=d & _docanchor= & _ct=62 & _acct=C000050221 & _version=1 & _urlVersion=0 & _userid=10 & md5=\

11142f68a2874f001ed7d08490b47828

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[Guest guest]

Clinical–Liver, Pancreas, and Biliary Tract

Regulatory Polymorphisms in the Promoter of CXCL10 Gene and Disease Progression

in Male Hepatitis B Virus rs

Guohong Deng‡, Gangqiao Zhou, §, Rong Zhang, Yun Zhai, §, Wenli Zhao‡, Zehui

Yan‡, Chunqing Deng‡, Xiaoyan Yuan, Baoyan Xu‡, Xiaojia Dong§, Xiumei Zhang,

Xuqing Zhang‡, Zhijian Yao§, Yan Shen§, Boqing Qiang§, Yuming Wang‡, , and

Fuchu He, §, ¶, ,

‡Department of Infectious Diseases, Southwest Hospital, Third Military Medical

University, Chongqing, China

State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing

Institute of Radiation Medicine, Beijing, China

Institute of Pathology, Southwest Hospital, Third Military Medical University,

Chongqing, China

§Chinese National Human Genome Center at Beijing, Beijing, China

¶Institute of Biomedical Sciences, Fudan University, Shanghai, China

Received 14 August 2007; accepted 13 December 2007. Available online 1 January

2008.

Background & Aims: 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-210A 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.

Abbreviations: ANOVA, analysis of variance; ChIP, chromatin immunoprecipitation;

CI, confidence interval; htSNP, haplotype-tagged single nucleotide polymorphism;

IFN, interferon; LD, linkage disequilibrium; OR, odds ratio; PCR, polymerase

chain reaction; SNP, single nucleotide polymorphism

G.D. and G.Z. contributed equally to this work. The Department of Infectious

Diseases, Southwest Hospital, and the State Key Laboratory of Proteomics,

Beijing Proteome Research Center contributed equally to this work.

Supported in part by grants from the Chinese High-tech Program (2006AA02A412),

Chinese National Natural Science Fund for Creative Research Groups Program

(30621063), Chinese National Basic Research Program (2006CB910803 and

2007CB512903), Beijing Science & Technology NOVA Program (2006A54), and Chinese

National Natural Science Foundation (30470964 and 30671850).

The authors report they have no conflicts of interest to disclose. The funding

sources had no role in study design, collection, analysis, or interpretation of

data; the writing of the report; or the decision to submit the report for

publication.

Address requests for reprints to: Fuchu He, PhD, State Key Laboratory of

Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation

Medicine, Beijing, 100850, P. R. China. fax: (86) 10-68177417

Yuming Wang, Department of Infectious Diseases, Southwest Hospital, Third

Military Medical University, Chongqing, 400038, P. R. China. fax: (86)

23-65334998.

Gastroenterology

Volume 134, Issue 3, March 2008, Pages 716-726.e2

http://www.sciencedirect.com/science?_ob=ArticleURL & _udi=B6WFX-4RGM0RK-1 & _user=1\

0 & _coverDate=03%2F31%2F2008 & _rdoc=19 & _fmt=summary & _orig=browse & _srch=doc-info(%2\

3toc%236806%232008%23998659996%23682098%23FLA%23display%23Volume) & _cdi=6806 & _sor\

t=d & _docanchor= & _ct=62 & _acct=C000050221 & _version=1 & _urlVersion=0 & _userid=10 & md5=\

11142f68a2874f001ed7d08490b47828

_________________________________________________________________

Connect and share in new ways with Windows Live.

http://www.windowslive.com/share.html?ocid=TXT_TAGHM_Wave2_sharelife_012008