title: Comparison of circulating, hepatocyte specific messenger RNA and microRNA as biomarkers for chronic hepatitis B and C.
abstract: Circulating microRNAs have been widely recognized as a novel category of biomarker in a variety of physiological and pathological conditions. Other reports revealed that fragments of organ specific messenger RNAs are also detectable in serum/plasma and can be utilized as sensitive indicators of liver pathology and cancer. In order to assess the sensitivity and reliability of these two class of RNAs as marker of hepatitis B or C induced chronic liver disease, we collected plasma samples from 156 chronic hepatitis B or C patients (HBV active n = 112, HBV carrier n = 19, hepatitis C n = 25) and 22 healthy donors and quantified their circulating mRNA for albumin, HP (haptoglobin), CYP2E1 (cytochrome P450, family 2, subfamily E) and ApoA2 (Apolipoprotein A2) in conjunction with microRNA-122, a well established marker for acute and chronic liver injury. We found that plasma microRNA-122 level is significantly elevated in patients with active HBV but not in HBV carriers. Furthermore, microRNA-122 is not elevated in HCV patients even though their median serum alanine aminotransferase (sALT) was three fold of the healthy donors. Nevertheless, circulating mRNAs, especially albumin mRNA, showed much more sensitivity in distinguishing active hepatitis B, hepatitis B carrier or HCV patients from healthy control. Correlation and multiple linear regression analysis suggested that circulating mRNAs and miRNAs are much more related to HBsAg titre than to sALT. Immunoprecipitation of HBsAg in HBV patients' plasma resulted in enrichment of albumin and HP mRNA suggesting that fragments of liver specific transcripts can be encapsidated into HBsAg particles. Taken together, our results suggest that hepatocyte specific transcripts in plasma like albumin mRNA showed greater sensitivity and specificity in differentiating HBV or HCV induced chronic liver disease than microRNA-122. Circulating mRNA fragments merit more attention in the quest of next generation biomarkers for various maladies.
authors.affiliation: Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Viral Hepatitis, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Zhanqing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Fahui
authors.initials: F
authors.lastname: Dai
authors.affiliation: Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Bisheng
authors.initials: B
authors.lastname: Shi
authors.affiliation: Department of Viral Hepatitis, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Infectious and Respiratory Diseases, School of Medicine, Shanghai Jiaotong University, Ruijin Hospital, Shanghai, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Sixth people's hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Zang
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jiming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Chinese Traditional Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Infectious Disease, Shanghai Changning Center Hospital, Shanghai, China.
authors.forename: Fangxing
authors.initials: F
authors.lastname: Qian
authors.affiliation: Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yunwen
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics; D016633:Apolipoprotein A-II / Q000097:blood / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002353:Carrier State; D016022:Case-Control Studies; D019392:Cytochrome P-450 CYP2E1 / Q000097:blood / Q000235:genetics; D003937:Diagnosis, Differential; D005260:Female; D015870:Gene Expression; D006242:Haptoglobins / Q000235:genetics / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000097:blood* / Q000235:genetics; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism
chemical_list: C115794:APOA2 protein, human; D016633:Apolipoprotein A-II; D015415:Biomarkers; C485359:HP protein, human; D006242:Haptoglobins; D006514:Hepatitis B Surface Antigens; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D012709:Serum Albumin; D019392:Cytochrome P-450 CYP2E1; D000410:Alanine Transaminase