Effects of variant rs346473 in ARHGAP24 gene on disease progression of HBV infection in han Chinese population

Abstract

Host genetic, environmental and viral factors are classified as three categories that determine clinical outcomes of hepatitis B virus (HBV) infection. The objective of this study was to detect the associations between polymorphisms rs346473 and rs346482 in Rho GTPase-activating protein 24 (ARHGAP24) gene and disease progression of HBV infection in Han Chinese population. These two SNPs were found by our DNA pooling using Affymetrix Genome-Wide Human Mapping SNP6.0 Array in HBV carriers, and verified by using TaqMan 7900HT Sequence Detection System with 758 progressed HBV carriers versus 300 asymptomatic HBV carriers (AsC) in a discovery phase and 971 progressed HBV carriers versus 328 AsC in a replication phase. Multivariable logistic regression revealed that individuals with genotype TT at variant rs346473 displayed remarkable correlations with disease progression of HBV infection both in the discovery phase (OR, 2.693; 95% CI, 1.928–3.760; P=6.2×10⁻⁹; additive model) and the replication phase (OR, 1.490; 95% CI, 1.104–2.012; P=9.0×10⁻³; additive model). These two SNPs were in strong linkage disequilibrium with D′=0.99 and r²=0.951, and haplotype TT disclosed an increased susceptibility to HBV progression (OR, 1.980; 95% CI, 1.538–2.545; P=8.1×10⁻⁸). These findings suggest that polymorphism rs346473 in the ARHGAP24 gene might be a part of the genetic variants underlying the susceptibility of HBV carriers to disease progression.

Keywords

ARHGAP24 gene / single nucleotide polymorphisms / HBV progression

References

[1] FrodshamA.J.. Host genetics and the outcome of hepatitis B viral infection. Transpl Immunol, 2005, 14(3–4): 183-186

[2] Prevention UCfDCa. CDC Travel’s Health-2010 Yellow Book, Chapter 2 - Hepatitis B. (updated 6 October 2009, Accessed 18 June 2010) available from http:/wwwnc.cdc.gov/travel/yellowbook/2010/Chapter 2/Hepatitis b.as px.

[3] ThurszM.. Genetic susceptibility in chronic viral hepatitis. Antiviral Res, 2001, 52(2): 113-116

[4] ChuC.J., LokA.S.. Clinical significance of hepatitis B virus genotypes. Hepatology, 2002, 35(5): 1274-1276

[5] BeasleyR.P.. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer, 1988, 61(10): 1942-1956

[6] GeierA., GartungC., DietrichC.G.. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med, 2002, 347(21): 1721-1722

[7] ChenC.J., YangH.I., IloejeU.H.. Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology, 2009, 49(5Suppl): S72-84

[8] HuX., LinJ., XieQ., et al.. DNA double-strand breaks, potential targets for HBV integration. J Huazhong Univ Sci Technolog Med Sci, 2010, 30(3): 265-270

[9] WangJ., LinJ., ChangY., et al.. MCM3AP, a novel HBV integration site in hepatocellular carcinoma and its implication in hepatocarcinogenesis. J Huazhong Univ Sci Technolog Med Sci, 2010, 30(4): 425-429

[10] LinT.M., ChenC.J., WuM.M., et al.. Hepatitis B virus markers in Chinese twins. Anticancer Res, 1989, 9(3): 737-741

[11] DemirG., BelentepeS., OzgurogluM., et al.. Simultaneous presentation of hepatocellular carcinoma in identical twin brothers. Med Oncol, 2002, 19(2): 113-116

[12] HeY.L., ZhaoY.R., ZhangS.L., et al.. Host susceptibility to persistent hepatitis B virus infection. World J Gastroenterol, 2006, 12(30): 4788-4793

[13] SamsonM., LibertF., DoranzB.J., et al.. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature, 1996, 382(6593): 722-725

[14] JinQ., AgrawalL., MeyerL., et al.. CCR5Delta32 59537-G/A promoter polymorphism is associated with low translational efficiency and the loss of CCR5Delta32 protective effects. J Virol, 2008, 82(5): 2418-2426

[15] KamataniY., WattanapokayakitS., OchiH., et al.. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet, 2009, 41(5): 591-595

[16] ZhangH., ZhaiY., HuZ., et al.. Genome-wide association study identifies 1p36. 22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet, 2010, 42(9): 755-758

[17] ParasitologyC.. The sixth Chinese national conference on virus hepatitis: prevention and treatment of virus hepatitis (draft). Chin J Internal Med, 2000, 44: 788-789

[18] GanemD., PrinceA.M.. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med, 2004, 350(11): 1118-1129

[19] MeaburnE., ButcherL.M., SchalkwykL.C., et al.. Genotyping pooled DNA using 100K SNP microarrays: a step towards genomewide association scans. Nucleic Acids Res, 2006, 34(4): e27

[20] PearsonJ.V., HuentelmanM.J., HalperinR.F., et al.. Identification of the genetic basis for complex disorders by use of pooling-based genomewide single-nucleotide-polymorphism association studies. Am J Hum Genet, 2007, 80(1): 126-139

[21] LovmarL., AhlfordA., JonssonM., et al.. Silhouette scores for assessment of SNP genotype clusters. BMC Genomics, 2005, 6: 35

[22] ShamP., BaderJ.S., CraigI., et al.. DNA Pooling: a tool for large-scale association studies. Nat Rev Genet, 2002, 3(11): 862-871

[23] BaumA.E., AkulaN., CabaneroM., et al.. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry, 2008, 13(2): 197-207

[24] ShifmanS., JohannessonM., BronsteinM., et al.. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet, 2008, 4(2): e28

[25] BosseY., BacotF., MontpetitA., et al.. Identification of susceptibility genes for complex diseases using pooling-based genome-wide association scans. Hum Genet, 2009, 125(3): 305-318

[26] HuoT., WuJ.C., HwangS.J., et al.. Factors predictive of liver cirrhosis in patients with chronic hepatitis B: a multivariate analysis in a longitudinal study. Eur J Gastroenterol Hepatol, 2000, 12(6): 687-693

[27] ChanH.L., TseC.H., MoF., et al.. High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma. J Clin Oncol, 2008, 26(2): 177-182

[28] ParkB.K., ParkY.N., AhnS.H., et al.. Long-term outcome of chronic hepatitis B based on histological grade and stage. J Gastroenterol Hepatol, 2007, 22(3): 383-388

[29] MoonS.Y., ZhengY.. Rho GTPase-activating proteins in cell regulation. Trends Cell Biol, 2003, 13(1): 13-22

[30] OhtaY., HartwigJ.H., StosselT.P.. FilGAP, a Rho- and ROCK-regulated GAP for Rac binds filamin A to control actin remodelling. Nat Cell Biol, 2006, 8(8): 803-814

[31] SuZ.J., HahnC.N., GoodallG.J., et al.. A vascular cell-restricted RhoGAP, p73RhoGAP, is a key regulator of angiogenesis. Proc Natl Acad Sci USA, 2004, 101(33): 12 212-12 217

[32] YingJ., LiH., CuiY., et al.. Epigenetic disruption of two proapoptotic genes MAPK10/JNK3 and PTPN13/FAP-1 in multiple lymphomas and carcinomas through hypermethylation of a common bidirectional promoter. Leukemia, 2006, 20(6): 1173-1175

[33] TournierC., HessP., YangD.D., et al.. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science, 2000, 288(5467): 870-874

[34] HolmH., GudbjartssonD.F., ArnarD.O., et al.. Several common variants modulate heart rate, PR interval and QRS duration. Nat Genet, 2010, 42(2): 117-122