Objective Genome-wide association studies (GWAS) have linked many single nucleotide polymorphisms (SNPs) to the outcomes of a variety of liver diseases. The aim of the present study was to evaluate the association of several candidate SNPs with the risk and severity of cirrhosis due to chronic hepatitis B in a Chinese population.
Methods A total of 714 Chinese participants with persistent HBV infection were studied. Patients were divided into cirrhotic (n = 429) and non-cirrhotic (n = 285) groups based on clinical and pathological evidence. The progression rate and severity of liver cirrhosis were evaluated with an arbitrary t-score system. Genotypes of six SNPs in five candidate genes were detected with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The genotypic distributions of the SNPs were compared between the age-matched cirrhotic and non-cirrhotic subjects. The association between the risk of SNPs and the severity and progression rate of cirrhosis was further analyzed.
Results Rs2679757 polymorphism of the antizyme inhibitor 1 (AZIN1) gene and Rs886277 in the transient receptor potential cation channel subfamily M, member 5 gene (TRPM5) were found to be associated with cirrhosis risk in CHB. They were also correlated with the overall severity and progression rate of cirrhosis. Genotype frequencies of other SNPs were not different between the cirrhosis and non-cirrhosis groups.
Conclusions AZIN1 rs2679757 and TRPM5 rs886277 are associated with the risk and the progression rate of HBV-related liver fibrosis in Chinese patients. The emerging SNPs associated with cirrhosis prognosis warrant further clinical validation in other CHB cohorts or ethnic groups, and merit mechanistic studies to reveal their roles in fibrosis progression.
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1 Poynard T Bedossa P Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC METAVIR CLINIVIR and DOSVIRC groups. Lancet 1997;349:825-832.
2 Powell EE Edwards-Smith CJ Hay JL Clouston AD Crawford DH Shorthouse C et al. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 2000;31:828-833.
3 Day CP. Genetic studies to identify hepatic fibrosis genes and SNPs i n human populations. Methods Mol Med 2005;117:315-331.
4 Karlsen TH Melum E Franke A. The utility of genome-wide association studies in hepatology. Hepatology 2010;51:1833-1842.
5 Huang H Shiffman ML Cheung RC Layden TJ Friedman S Abar OT et al. Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C. Gastroenterology 2006;130:1679-1687.
6 Huang H Shiffman ML Friedman S Venkatesh R Bzowej N Abar OT et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 2007;46:297-306.
7 Marcolongo M Young B Dal Pero F Fattovich G Peraro L Guido M et al. A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C. Hepatology 2009;50:1038-1044.
8 Curto TM Lagier RJ Lok AS Everhart JE Rowland CM Sninsky JJ et al. Predicting cirrhosis and clinical outcomes in patients with advanced chronic hepatitis C with a panel of genetic markers (CRS7). Pharmacogenet Genomics 2011;21:851-860.
9 Shepard CW Simard EP Finelli L Fiore AE Bell BP. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol Rev 2006;28:112-125.
10 Chen CJ Wang LY Yu MW. Epidemiology of hepatitis B virus infection in the Asia-Pacific region. J Gastroenterol Hepatol 2000;15 Suppl:e3-e6.
11 Lavanchy D. Hepatitis B virus epidemiology disease burden treatment and current and emerging prevention and control measures. J Viral Hepat 2004;11:97-107.
12 Yuen MF Sablon E Yuan HJ Wong DK Hui CK Wong BC et al. Significance of hepatitis B genotype in acute exacerbation HBeAg seroconversion cirrhosis-related complications and hepatocellular carcinoma. Hepatology 2003;37:562-567.
13 Yin JH Zhao J Zhang HW Xie JX Li WP Xu GZ et al. HBV genotype C is independently associated with cirrhosis in community-based population. World J Gastroenterol 2010;16:379-383.
14 Takata K. Aquaporin-2 (AQP2): its intracellular compartment and trafficking. Cell Mol Biol 2006;52:34-39.
15 Mangold U. Antizyme inhibitor: mysterious modulator of cell proliferation. Cell Mol Life Sci 2006;63:2095-2101.
16 Ternes P Franke S Zahringer U Sperling P Heinz E. Identification and characterization of a sphingolipid delta 4-desaturase family. J Biol Chem 2002;277:25512-25518.
17 Kraveka JM Li L Szulc ZM Bielawski J Ogretmen B Hannun YA et al. Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J Biol Chem 2007;282:16718-16728.
18 Li Y Chang M Abar O Garcia V Rowland C Catanese J et al. Multiple variants in toll-like receptor 4 gene modulate risk of liver fibrosis in Caucasians with chronic hepatitis C infection. J Hepatol 2009;51:750-757.
19 Beutler B. Inferences questions and possibilities in Toll-like receptor signalling. Nature 2004;430:257-263.
20 Seki E De Minicis S Osterreicher CH Kluwe J Osawa Y Brenner DA et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007;13:1324-1332.
21 Guo J Loke J Zheng F Hong F Yea S Fukata M et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology 2009;49:960-968.
22 Kaske S Krasteva G König P Kummer W Hofmann T Gudermann T et al. TRPM5 a taste-signaling transient receptor potential ion-channel is a ubiquitous signaling component in chemosensory cells. BMC Neurosci 2007; 8:49.
23 Jurinke C Oeth P van den Boom D. MALDI-TOF Mass Spectrometry. Mol Biotech 2004;26:147-163.
24 Ragoussis J Elvidge GP Kaur K Colella S. Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry in genomics research. PLoS Genet 2006;2:e100.
25 Paris AJ Snapir Z Christopherson CD Kwok SY Lee UE Ghiassi-Nejad Z et al. A polymorphism that delays fibrosis in hepatitis C promotes alternative splicing of AZIN1 reducing fibrogenesis. Hepatology 2011;54: 2198-2207.
26 Prawitt D Monteilh-Zoller MK Brixel L Spangenberg C Zabel B Fleig A et al. TRPM5 is a transient Ca2+-activated cation channel responding to rapid changes in [Ca2+]i. Proc Natl Acad Sci USA 2003;100:15166-15171.