基于SNP-MaP慢性乙型肝炎不同临床转归全基因组关联研究和乙型重型肝炎预后模型的构建
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摘要
目的：慢性乙型肝炎的临床转归包括乙肝病毒携带者肝、硬化、肝癌、乙型重型肝炎,它是一组有明确病因的复杂多基因疾病,应用SNP-MaP(snp microarray and pooling)完成全基因组扫描,寻找慢性乙型肝炎重症化的易感位点,并扩大样本验证其易感性位点。
方法：根据慢性乙型肝炎的临床转归的表型将样本分为乙肝病毒携带者,肝硬化,肝癌,乙型重型肝炎。应用affymatrix SNP 6.0扫描各组中100个样本随机挑选86个组成DNA pool,并完成3个生物学重复。分别运用两种不同的统计学方法进行分析,挑选差异性最强的SNP位点。在乙肝病毒携带者234例,肝硬化300例,肝癌300例,乙型重型肝炎171例进行个体验证。
结果：通过严格的统计学挑选,一共挑选7个SNP进行个体的基因分型。发现两个与肝硬化易感性的多态性位点分别是转录因子TBX5 SNP位点rs3825214在于对照组相比(共显性模型P=0.024,显性模型P=0.008 OR1.8(1.1-2.9))和膜蛋白SCUBE3 SNP位点rs 3800385在于对照组相比(显性模型P=0.0076 OR 1.6(1.1-2.32)).且SNP位点rs3800385在肝癌在于对照组相比较的共显性模型中具有统计学意义
结论：从分子流行病学的角度证明了TBX5和SCUBE3在肝硬化易感性中起重要作用。SCUBE3与肝癌的易感性相关。
目的：前瞻性随访乙型重型肝炎病人长期预后,并对影响乙型重型肝炎长期预的危险因素进行分析,从中筛选出对预后有明显影响的因素,构建预后模型并与现有的预后模型进行对比其预后判断效能,在一个独立回顾性的样本进行验证,判断对预后预测的准确性。
方法：从2007年6月到2008年12月前瞻性从4个医院进行样本收集254例乙型重型肝炎病人,同样的时间段内在回顾性中心收集乙型重型肝炎病例43例,记录所有的临床资料对上述病人情况进行随访。记录所有的住院期间临床资料。依据随访的结果,分析生化指标和并发症对死亡的影响,同时探讨肝硬化重型肝炎程与非肝硬化重型肝炎临床指标的差异。应用单因素分析和多元回归模型,建立预后模型,运用ROC曲线下面积比较本研究的模型与现有的重型肝炎预后模型预测能力。然后在回顾性的中心验证预后模型的预测效能。
结果：前瞻性中心平均年龄为40.58(14-69)肝硬化比例为27.16%,男性比例为88.89%,而回顾性中心平均年龄为43.3(20-66)肝硬化比例为27.9%,男性比例为90.7%。随访截止时间为2009年12月,平均随访时间为19.5(0-30)。总的生存率为34.68%,其中前瞻性中心的生存率为35.03%而回顾性的中心生存率为32.58%。分析发现生存组和死亡组中年龄、凝血酶原时间、凝血酶原活动度、纤维蛋白原、总胆红素、直接胆红素、血清γ谷氨酰转肽酶、乳酸脱氢酶、氯、肌酐、MELD评分、肝硬化、脾大、自发性腹膜炎、腹水、肝性脑病、肝肾综合症均有统计学差异(P<0.05)。而在肝硬化组和非肝硬化组中年龄、感染周数、凝血酶原时间、国际化标准比值、凝血酶原活动度、谷丙转氨酶、谷草转氨酶、胆固醇、肌酐、尿酸、HBV-DNA.MELD评分、死亡率上均有统计学差异(P<0.05),多因素回归分析构建预后模型P=eX／1+eX,X=(4.542+0.671*国际化标准比值+0.003*总胆红素mmol／L+0.034*肌酐mmol／L-0.025*氯mmol／L+0.445*肝硬化),在ROC曲线下面积比较,本研究模型ROC面积较MELD评分系统,Dhiman模型,Sun模型及西安标准曲线下面积显著性大于(P<0.05)，依次为(0.80,CI95%0.75-0.86),MELD(0.73,CI95%0.67-0.8),Sun(0.71,CI 95%0.64-0.7791,Dhiman模型(0.66,CI 95%0.61-0.71),西安标准(0.58,CI95%0.528-0.65)。重复在回顾性的中心进行验证发现本研究的模型ROC曲线下面积0.93大于MELD 0.87.
结论：本研究模型在乙型重型肝炎预后预测上优于MELD等预后模型,乙型重型肝炎并发症不能作为预后模型,由于并发症因其发生率较低且出现较晚。肝硬化乙型重型肝炎用于预后模型构建是可行的。
Objectives:the adverse outcomes of chronic HBV infection are a polygenic trait. We performed a genome-wide screen to identify progression related variants in the respective adverse outcomes including HBV carrier, cirrhosis, liver cancer and acute liver failure.
Methods:The initial genome-wide screen by affymatrix SNP 6.0 was done in pooled DNA in randomly selected 86 individual from 100 samples among each outcome. SNPs fulfilling the selection criteria of the pooling stage were genotyped individually in this same sample and additional sample, of which totally included heath HBV carrier 234、cirrhosis 300、liver cancer 300 and acute liver failure 171.
Results:we combined two different and stringent statistical approaches (a single-point method and, as a filter for the most significant SNPs, a sliding-window method) to select SNPs of high statistical confidence, finally 7 SNPs is genotyped individually, two genomic loci encoding TBX5 rs382514(additive model P=0.024, dominant model P=0.008 OR 1.8(1.1-2.9)) and SCUBE3 rs 3800385 (additive model P=0.02, dominant model P=0.0076 OR 1.6(1.1-2.32)) was significantly associated with cirrhosis. And SNP rs3800385 of SCUBE3 is significant associated with liver cancer in additive model.
Conclusions:Two-stage genetic analysis from above experiments suggests a role for TBX5 and SCUBE3 in HBV-related cirrhosis.
Objectives:To describe and analyze the clinical features, complications and follow-up outcomes of HBV-related acute liver failure.To establish prognositic model according to results of follow-up study and compare with current acute liver failure prognositic models such from MELD, Sun, Dhiman prognositic model.To validate accuracy of our model in a indenpent retrospective corhort.
Methods:Prospective cohort study consisted of 4 hospital and retrospective cohort included 2 hospital,254 and 43 consecutive patients with acute liver failure admitted over the same 18-month period from the prospective cohort and retrospective cohort respectively.Detailed clinical, Laboratory data and complications collected and analyzed the significant diffence between survival vs. nosurvival group and cirrhosis vs. nocirrhosis group. Logistic regression was also carried out to build prognositic model. Compared our model with current prognostic models by ROC curve, and to validate its predicting accuracy in retrospective independent cohort.
Results:The median age of the prospective and retrospective was 40.58 (14-69) and 43.3(20-66) respectively; Cirrhostic rate in prospective group and retrospective group is 27.16% and 27.9% respectively; the overall group was predominantly male 88.89% and 90.7% in prospective group and retrospective group respectively.The follow-up study time is averagely 19.5 (0-30) months from time discharge from hospital and the censored time is Dec,2009. Overall survival rate was 34.68%(103 of total 297), and 35.03% in prospective group and 32.58% in retrospective group Independent risk analysis in survival and nosurvivor goup indicated age, PT, PTA,Fb, Total Bilirubin, DB, GGT, Lactate dehydrogenase, Chlorine, Creatinine,MELD; and Complication of Splenomegaly, Peritonitis, Ascites, Hepatic encephalopathy, Hepatorenal syndrome, Cirrhosis was significant between survival group and death group, the difference of clinical characteristics also existed in cirrhostic and nocirrhostic patients.multiple logistic regression applied to create prognositic model, the model comes to P= eX/1+eX, (X=4.542+0.671*INR+0.003*TB mmol/L-0.025*chlorinemmol/L +0.034*creatinine mmol/L+0.445*Cirrhosis). From the ROC curves, it was found that ROC of our model (0.8, confidence interval 95% 0.75-0.86) is significantly superior to MELD (0.73, confidence interval 95% 0.67-0.8) which is better than Sun Model (0.71, confidence interval 95%0.64-0.77), Dhiman model (0.66, confidence interval 95% 0.61-0.71) and China model (0.58, confidence interval 95% 0.52-0.65), To validite the accuracy of our model in predicting prognosis,43 patients from restrospective group was analyzed, and compared our model with MELD scoring system which was better than other prognostic models in our study, the result displayed AUC of our model was 0.9368 compared to 0.8776 of MELD
Conclusions:our model is superior to MELD in predicting survival rate of HBV-related acute liver failure.complications of the HBV-induced acute liver can not be proposed as prognostic factors for its low incidence and end-stage occurrence. Consideration of cirrhosis in prognositc model building is feasible and necessary in China.
Key Words:prognosis; hepatitis B virus; prognostic model; follow-up study
方法：根据慢性乙型肝炎的临床转归的表型将样本分为乙肝病毒携带者,肝硬化,肝癌,乙型重型肝炎。应用affymatrix SNP 6.0扫描各组中100个样本随机挑选86个组成DNA pool,并完成3个生物学重复。分别运用两种不同的统计学方法进行分析,挑选差异性最强的SNP位点。在乙肝病毒携带者234例,肝硬化300例,肝癌300例,乙型重型肝炎171例进行个体验证。
结果：通过严格的统计学挑选,一共挑选7个SNP进行个体的基因分型。发现两个与肝硬化易感性的多态性位点分别是转录因子TBX5 SNP位点rs3825214在于对照组相比(共显性模型P=0.024,显性模型P=0.008 OR1.8(1.1-2.9))和膜蛋白SCUBE3 SNP位点rs 3800385在于对照组相比(显性模型P=0.0076 OR 1.6(1.1-2.32)).且SNP位点rs3800385在肝癌在于对照组相比较的共显性模型中具有统计学意义
结论：从分子流行病学的角度证明了TBX5和SCUBE3在肝硬化易感性中起重要作用。SCUBE3与肝癌的易感性相关。
目的：前瞻性随访乙型重型肝炎病人长期预后,并对影响乙型重型肝炎长期预的危险因素进行分析,从中筛选出对预后有明显影响的因素,构建预后模型并与现有的预后模型进行对比其预后判断效能,在一个独立回顾性的样本进行验证,判断对预后预测的准确性。
方法：从2007年6月到2008年12月前瞻性从4个医院进行样本收集254例乙型重型肝炎病人,同样的时间段内在回顾性中心收集乙型重型肝炎病例43例,记录所有的临床资料对上述病人情况进行随访。记录所有的住院期间临床资料。依据随访的结果,分析生化指标和并发症对死亡的影响,同时探讨肝硬化重型肝炎程与非肝硬化重型肝炎临床指标的差异。应用单因素分析和多元回归模型,建立预后模型,运用ROC曲线下面积比较本研究的模型与现有的重型肝炎预后模型预测能力。然后在回顾性的中心验证预后模型的预测效能。
结果：前瞻性中心平均年龄为40.58(14-69)肝硬化比例为27.16%,男性比例为88.89%,而回顾性中心平均年龄为43.3(20-66)肝硬化比例为27.9%,男性比例为90.7%。随访截止时间为2009年12月,平均随访时间为19.5(0-30)。总的生存率为34.68%,其中前瞻性中心的生存率为35.03%而回顾性的中心生存率为32.58%。分析发现生存组和死亡组中年龄、凝血酶原时间、凝血酶原活动度、纤维蛋白原、总胆红素、直接胆红素、血清γ谷氨酰转肽酶、乳酸脱氢酶、氯、肌酐、MELD评分、肝硬化、脾大、自发性腹膜炎、腹水、肝性脑病、肝肾综合症均有统计学差异(P<0.05)。而在肝硬化组和非肝硬化组中年龄、感染周数、凝血酶原时间、国际化标准比值、凝血酶原活动度、谷丙转氨酶、谷草转氨酶、胆固醇、肌酐、尿酸、HBV-DNA.MELD评分、死亡率上均有统计学差异(P<0.05),多因素回归分析构建预后模型P=eX／1+eX,X=(4.542+0.671*国际化标准比值+0.003*总胆红素mmol／L+0.034*肌酐mmol／L-0.025*氯mmol／L+0.445*肝硬化),在ROC曲线下面积比较,本研究模型ROC面积较MELD评分系统,Dhiman模型,Sun模型及西安标准曲线下面积显著性大于(P<0.05)，依次为(0.80,CI95%0.75-0.86),MELD(0.73,CI95%0.67-0.8),Sun(0.71,CI 95%0.64-0.7791,Dhiman模型(0.66,CI 95%0.61-0.71),西安标准(0.58,CI95%0.528-0.65)。重复在回顾性的中心进行验证发现本研究的模型ROC曲线下面积0.93大于MELD 0.87.
结论：本研究模型在乙型重型肝炎预后预测上优于MELD等预后模型,乙型重型肝炎并发症不能作为预后模型,由于并发症因其发生率较低且出现较晚。肝硬化乙型重型肝炎用于预后模型构建是可行的。
Objectives:the adverse outcomes of chronic HBV infection are a polygenic trait. We performed a genome-wide screen to identify progression related variants in the respective adverse outcomes including HBV carrier, cirrhosis, liver cancer and acute liver failure.
Methods:The initial genome-wide screen by affymatrix SNP 6.0 was done in pooled DNA in randomly selected 86 individual from 100 samples among each outcome. SNPs fulfilling the selection criteria of the pooling stage were genotyped individually in this same sample and additional sample, of which totally included heath HBV carrier 234、cirrhosis 300、liver cancer 300 and acute liver failure 171.
Results:we combined two different and stringent statistical approaches (a single-point method and, as a filter for the most significant SNPs, a sliding-window method) to select SNPs of high statistical confidence, finally 7 SNPs is genotyped individually, two genomic loci encoding TBX5 rs382514(additive model P=0.024, dominant model P=0.008 OR 1.8(1.1-2.9)) and SCUBE3 rs 3800385 (additive model P=0.02, dominant model P=0.0076 OR 1.6(1.1-2.32)) was significantly associated with cirrhosis. And SNP rs3800385 of SCUBE3 is significant associated with liver cancer in additive model.
Conclusions:Two-stage genetic analysis from above experiments suggests a role for TBX5 and SCUBE3 in HBV-related cirrhosis.
Objectives:To describe and analyze the clinical features, complications and follow-up outcomes of HBV-related acute liver failure.To establish prognositic model according to results of follow-up study and compare with current acute liver failure prognositic models such from MELD, Sun, Dhiman prognositic model.To validate accuracy of our model in a indenpent retrospective corhort.
Methods:Prospective cohort study consisted of 4 hospital and retrospective cohort included 2 hospital,254 and 43 consecutive patients with acute liver failure admitted over the same 18-month period from the prospective cohort and retrospective cohort respectively.Detailed clinical, Laboratory data and complications collected and analyzed the significant diffence between survival vs. nosurvival group and cirrhosis vs. nocirrhosis group. Logistic regression was also carried out to build prognositic model. Compared our model with current prognostic models by ROC curve, and to validate its predicting accuracy in retrospective independent cohort.
Results:The median age of the prospective and retrospective was 40.58 (14-69) and 43.3(20-66) respectively; Cirrhostic rate in prospective group and retrospective group is 27.16% and 27.9% respectively; the overall group was predominantly male 88.89% and 90.7% in prospective group and retrospective group respectively.The follow-up study time is averagely 19.5 (0-30) months from time discharge from hospital and the censored time is Dec,2009. Overall survival rate was 34.68%(103 of total 297), and 35.03% in prospective group and 32.58% in retrospective group Independent risk analysis in survival and nosurvivor goup indicated age, PT, PTA,Fb, Total Bilirubin, DB, GGT, Lactate dehydrogenase, Chlorine, Creatinine,MELD; and Complication of Splenomegaly, Peritonitis, Ascites, Hepatic encephalopathy, Hepatorenal syndrome, Cirrhosis was significant between survival group and death group, the difference of clinical characteristics also existed in cirrhostic and nocirrhostic patients.multiple logistic regression applied to create prognositic model, the model comes to P= eX/1+eX, (X=4.542+0.671*INR+0.003*TB mmol/L-0.025*chlorinemmol/L +0.034*creatinine mmol/L+0.445*Cirrhosis). From the ROC curves, it was found that ROC of our model (0.8, confidence interval 95% 0.75-0.86) is significantly superior to MELD (0.73, confidence interval 95% 0.67-0.8) which is better than Sun Model (0.71, confidence interval 95%0.64-0.77), Dhiman model (0.66, confidence interval 95% 0.61-0.71) and China model (0.58, confidence interval 95% 0.52-0.65), To validite the accuracy of our model in predicting prognosis,43 patients from restrospective group was analyzed, and compared our model with MELD scoring system which was better than other prognostic models in our study, the result displayed AUC of our model was 0.9368 compared to 0.8776 of MELD
Conclusions:our model is superior to MELD in predicting survival rate of HBV-related acute liver failure.complications of the HBV-induced acute liver can not be proposed as prognostic factors for its low incidence and end-stage occurrence. Consideration of cirrhosis in prognositc model building is feasible and necessary in China.
Key Words:prognosis; hepatitis B virus; prognostic model; follow-up study
引文
1. Lai, C.L. and M.F. Yuen, Chronic hepatitis B-new goals, new treatment. N Engl J Med,2008.359(23):p.2488-91.
2. Lok, A.S. and B.J. McMahon, Chronic hepatitis B. Hepatology,2007.45(2):p. 507-39.
3. Lok, A.S. and B.J. McMahon, Chronic hepatitis B:update 2009. Hepatology,2009. 50(3):p.661-2.
4. Ganem, D. and A.M. Prince, Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med,2004.350(11):p.1118-29.
5. McMahon, B.J., The natural history of chronic hepatitis B virus infection. Semin Liver Dis,2004.24 Suppl 1:p.17-21.
6. McMahon, B.J., Epidemiology and natural history of hepatitis B. Semin Liver Dis, 2005.25 Suppl 1:p.3-8.
7. McMahon, B.J., The natural history of chronic hepatitis B virus infection. Hepatology,2009.49(5 Suppl):p. S45-55.
8. Taylor, B.C., et al., Clinical outcomes in adults with chronic hepatitis B in association with patient and viral characteristics:A systematic review of evidence. Hepatology,2009.49(5 Suppl):p. S85-95.
9. Gandhi, M.J., et al., Hepatitis B virions isolated with antibodies to the pre-S1 domain reveal occult viremia by PCR in Alaska Native HBV carriers who have seroconverted. Transfusion,2000.40(8):p.910-6.
10. Liang, T.J., et al., Hepatitis B virus precore mutation and fulminant hepatitis in the United States. A polymerase chain reaction-based assay for the detection of specific mutation. J Clin Invest,1994.93(2):p.550-5.
11. Livingston, S.E., et al., Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology,2007.133(5):p. 1452-7.
12. McMahon, B.J., et al., A comprehensive programme to reduce the incidence of hepatitis B virus infection and its sequelae in Alaskan natives. Lancet,1987. 2(8568):p.1134-6.
13. Deng, G., et al., Regulatory polymorphisms in the promoter of CXCL10 gene and disease progression in male hepatitis B virus carriers. Gastroenterology,2008. 134(3):p.716-26.
14. Deng, G., et al., Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology,2004.40(2):p. 318-26.
15. Dong, X., et al., Association of DLC1 gene polymorphism with susceptibility to hepatocellular carcinoma in Chinese hepatitis B virus carriers. Cancer Epidemiol, 2009.33(3-4):p.265-70.
16. Kamatani, Y., 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):p.591-5.
17. Hirankarn, N., et al., Association of interleukin-18 gene polymorphism (-607A/A genotype) with susceptibility to chronic hepatitis B virus infection. Tissue Antigens, 2007.70(2):p.160-3.
18. Hohler, T., et al., A tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated with chronic hepatitis B infection. Clin Exp Immunol, 1998.111(3):p.579-82.
19. Kacprzak-Bergman, I. and J. Halasa, Polymorphism of the fourth component of complement (C4) and three clinical pictures of hepatitis B virus infection in children. Arch Immunol Ther Exp (Warsz),1997.45(4):p.295-300.
20. Lei, R.X., et al., Influence of a single nucleotide polymorphism in the P1 promoter of the furin gene on transcription activity and hepatitis B virus infection. Hepatology, 2009.50(3):p.763-71.
21. Park, J.S., et al., [Association of interleukin-12 gene polymorphism with persistence of hepatitis B virus infection and hepatocellular carcinoma]. Korean J Gastroenterol, 2007.50(5):p.313-8.
22. Ramezani, A., et al., Association of human leukocyte antigen polymorphism with outcomes of hepatitis B virus infection. J Gastroenterol Hepatol,2008.23(11):p. 1716-21.
23. Ribeiro, C.S., J.E. Visentainer, and R.A. Moliterno, Association of cytokine genetic polymorphism with hepatitis B infection evolution in adult patients. Mem Inst Oswaldo Cruz,2007.102(4):p.435-40.
24. Somi, M.H., et al., Tumor necrosis factor-alpha gene promoter polymorphism in Iranian patients with chronic hepatitis B. Indian J Gastroenterol,2006.25(1):p. 14-5.
25. The International HapMap Project. Nature,2003.426(6968):p.789-96.
26. A haplotype map of the human genome. Nature,2005.437(7063):p.1299-320.
27. Liu, L., et al., [Study of the quasispecies dynamics of serum hepatitis B virus in a patient with acute exacerbations of chronic hepatitis B]. Zhonghua Gan Zang Bing Za Zhi,2006.14(1):p.29-32.
28. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet,2009.41(7):p.824-8.
29. Barrett, J.C., et al., Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet,2009.
30. Barrett, J.C., et al., Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet,2008.40(8):p.955-62.
31. Xu, X., et al., DNA pooling analysis of 21 norepinephrine transporter gene SNPs with attention deficit hyperactivity disorder:no evidence for association. Am J Med Genet B Neuropsychiatr Genet,2005.134B(1):p.115-8.
32. Butcher, L.M., et al., Association analysis of mild mental impairment using DNA pooling to screen 432 brain-expressed single-nucleotide polymorphisms. Mol Psychiatry,2005.10(4):p.384-92.
33. Sham, P., et al., DNA Pooling:a tool for large-scale association studies. Nat Rev Genet,2002.3(11):p.862-71.
34. Barratt, B.J., et al., Identification of the sources of error in allele frequency estimations from pooled DNA indicates an optimal experimental design. Ann Hum Genet,2002.66(Pt 5-6):p.393-405.
35. Docherty, S.J., et al., Applicability of DNA pools on 500 K SNP microarrays for cost-effective initial screens in genomewide association studies. BMC Genomics, 2007.8:p.214.
36. Permutt, M.A., et al., Searching for type 2 diabetes genes on chromosome 20. Diabetes,2002.51 Suppl 3:p. S308-15.
37. Visscher, P.M. and S. Le Hellard, Simple method to analyze SNP-based association studies using DNA pools. Genet Epidemiol,2003.24(4):p.291-6.
38. Kirov, G, et al., A genome-wide association study in 574 schizophrenia trios using DNA pooling. Mol Psychiatry,2009.14(8):p.796-803.
39. Pearson, J.V., 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):p.126-39.
40. Fabris, C., et al., Gene polymorphism at the interleukin 6-174 G> C locus affects the outcome of chronic hepatitis B. J Infect,2009.59(2):p.144-5.
41. Hardie, D.R., J. Kannemeyer, and L.M. Stannard, DNA single strand conformation polymorphism identifies five defined strains of hepatitis B virus (HBV) during an outbreak of HBV infection in an oncology unit. J Med Virol,1996.49(1):p.49-54.
42. Yu, M.W., et al., A p53 genetic polymorphism as a modulator of hepatocellular carcinoma risk in relation to chronic liver disease, familial tendency, and cigarette smoking in hepatitis B carriers. Hepatology,1999.29(3):p.697-702.
43. Zhou, J., et al., A non-synonymous single nucleotide polymorphism in IFNAR1 affects susceptibility to chronic hepatitis B virus infection. J Viral Hepat,2009. 16(1):p.45-52.
44. Zhu, Z.Z., et al., A p53 polymorphism modifies the risk of hepatocellular carcinoma among non-carriers but not carriers of chronic hepatitis B virus infection. Cancer Lett,2005.229(1):p.77-83.
45. Skol, A.D., et al., Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet,2006.38(2):p.209-13.
46. Papassotiropoulos, A., et al., Common Kibra alleles are associated with human memory performance. Science,2006.314(5798):p.475-8.
47. Abdulla, M.A., et al., Mapping human genetic diversity in Asia. Science,2009. 326(5959):p.1541-5.
48. Xu, S., et al., Genomic dissection of population substructure of Han Chinese and its implication in association studies. Am J Hum Genet,2009.85(6):p.762-74.
49. Gu, J.W., et al., Long-term High Salt Diet Causes Hypertension and Decreases Renal Expression of Vascular Endothelial Growth Factor in Sprague-Dawley Rats. J Am Soc Hypertens,2008.2(4):p.275-85.
50. Koga, Y., et al., High salt intake enhances blood pressure increase during development of hypertension via oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats. Hypertens Res,2008.31(11):p.2075-83.
51. Mori, T., et al., High perfusion pressure accelerates renal injury in salt-sensitive hypertension. J Am Soc Nephrol,2008.19(8):p.1472-82.
52. Campese, V.M., et al., High salt intake inhibits nitric oxide synthase expression and aggravates hypertension in rats with chronic renal failure. J Nephrol,2002.15(4):p. 407-13.
53. Agarwal, M.M., et al., Gestational diabetes:fasting capillary glucose as a screening test in a multi-ethnic, high-risk population. Diabet Med,2009.26(8):p.760-5.
54. Cambuli, V.M., et al., Oral glucose tolerance test in Italian overweight/obese children and adolescents results in a very high prevalence of impaired fasting glycaemia, but not of diabetes. Diabetes Metab Res Rev,2009.25(6):p.528-34.
55. Ferland, A., et al., Impact of high-fat/low-carbohydrate, high-, low-glycaemic index or low-caloric meals on glucose regulation during aerobic exercise in Type 2 diabetes. Diabet Med,2009.26(6):p.589-95.
56. Modugno, F., et al., Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer. Int J Cancer,2006.118(5):p.1292-301.
57. Sasco, A.J., R. Kaaks, and R.E. Little, Breast cancer:occurrence, risk factors and hormone metabolism. Expert Rev Anticancer Ther,2003.3(4):p.546-62.
58. Bradlow, H.L., et al., Workshop on hormones, hormone metabolism, the environment, and breast cancer. J Natl Cancer Inst,1998.90(1):p.67.
59. Watanabe, M., et al., Congenital anomalies in a child born from a mother with interferon-treated chronic hepatitis B. Am J Gastroenterol,2001.96(5):p.1668-9.
60. Oren, H., O. Duzovali, and G Irken, Recombinant alpha-2a interferon treatment in a child with T-cell leukemia and chronic hepatitis B. Ann Hematol,1998.77(4):p. 187-90.
61. Basson, C.T., et al., Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet,1997.15(1):p.30-5.
62. Li, Q.Y., et al., Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet,1997.15(1):p.21-9.
63. Takeuchi, J.K., et al., Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis. Development,2003.130(24):p.5953-64.
64. Plageman, T.F., Jr. and K.E. Yutzey, Microarray analysis of Tbx5-induced genes expressed in the developing heart. Dev Dyn,2006.235(10):p.2868-80.
65. Goetz, S.C., D.D. Brown, and F.L. Conlon, TBX5 is required for embryonic cardiac cell cycle progression. Development,2006.133(13):p.2575-84.
66. Liberatore, C.M., R.D. Searcy-Schrick, and K.E. Yutzey, Ventricular expression of tbx5 inhibits normal heart chamber development. Dev Biol,2000.223(1):p. 169-80.
67. Maitra, M., et al., Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Dev Biol,2009.326(2):p.368-77.
68. Moskowitz, I.P., et al., A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development. Cell,2007.129(7):p. 1365-76.
69. Hiroi, Y., et al., Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet,2001.28(3):p.276-80.
70. Liu, C.X., et al., Association of TBX5 gene polymorphism with ventricular septal defect in the Chinese Han population. Chin Med J (Engl),2009.122(1):p.30-4.
71. Wu, B.T., et al., A novel secreted, cell-surface glycoprotein containing multiple epidermal growth factor-like repeats and one CUB domain is highly expressed in primary osteoblasts and bones. J Biol Chem,2004.279(36):p.37485-90.
72. Haworth, K., et al., Expression of the Scube3 epidermal growth factor-related gene during early embryonic development in the mouse. Gene Expr Patterns,2007.7(5): p.630-4.
1. Polson, J. and W.M. Lee, AASLD position paper:the management of acute liver failure. Hepatology,2005.41(5):p.1179-97.
2. Ostapowicz, G., et al., Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med,2002.137(12):p. 947-54.
3. McMahon, B.J., The natural history of chronic hepatitis B virus infection. Hepatology,2009.49(5 Suppl):p. S45-55.
4. Jalan, R. and R. Williams, Bio-artificial liver support for acute liver failure:should we be using it to treat patients? Transplantation,2002.73(2):p.165-6.
5. Girlanda, R., et al., Long-term outcome of immunosuppression withdrawal after liver transplantation. Transplant Proc,2005.37(4):p.1708-9.
6. Adam, R., et al., Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study. Lancet,2000.356(9230):p.621-7.
7. Williams, R., Changing clinical patterns in acute liver failure. J Hepatol,2003. 39(4):p.660-1.
8. O'Grady, J.G., et al., Early indicators of prognosis in fulminant hepatic failure. Gastroenterology,1989.97(2):p.439-45.
9. O'Grady, J.G., Pathogenesis of acute liver failure. Trop Gastroenterol,1996.17(4):p. 199-201.
10. Yu, J.W., et al., Prediction value of model for end-stage liver disease scoring system on prognosis in patients with acute-on-chronic hepatitis B liver failure after plasma exchange and lamivudine treatment. J Gastroenterol Hepatol,2008.23(8 Pt 1):p. 1242-9.
11. Yu, J.W., GQ. Wang, and S.C. Li, Prediction of the prognosis in patients with acute-on-chronic hepatitis using the MELD scoring system. J Gastroenterol Hepatol, 2006.21(10):p.1519-24.
12. Saigal, S., et al., Auxiliary partial orthotopic liver transplantation in acute liver failure due to hepatitis B. Transpl Int,2002.15(7):p.369-73.
13. Sun, Q.F., et al., Prediction of the prognosis of patients with acute-on-chronic hepatitis B liver failure using the model for end-stage liver disease scoring system and a novel logistic regression model. J Viral Hepat,2009.16(7):p.464-70.
14. Li, X.M., et al., Analyses of prognostic indices of chronic liver failure caused by hepatitis virus. World J Gastroenterol,2005.11(18):p.2841-3.
15. Schiodt, F.V., et al., Alpha-fetoprotein and prognosis in acute liver failure. Liver Transpl,2006.12(12):p.1776-81.
16. O'Grady, J.G, Fulminant hepatitis in patients with chronic liver disease. J Viral Hepat,2000.7 Suppl 1:p.9-10.
17. Dhiman, R.K., et al., Early indicators of prognosis in fulminant hepatic failure:an assessment of the Model for End-Stage Liver Disease (MELD) and King's College Hospital criteria. Liver Transpl,2007.13(6):p.814-21.
18. Anand, A.C., P. Nightingale, and J.M. Neuberger, Early indicators of prognosis in fulminant hepatic failure:an assessment of the King's criteria. J Hepatol,1997. 26(1):p.62-8.
19. Taylor, B.C., et al., Clinical outcomes in adults with chronic hepatitis B in association with patient and viral characteristics:A systematic review of evidence. Hepatology,2009.49(5 Suppl):p. S85-95.
20. Mauss, S., Therapy of chronic hepatitis B:new goals and new treatments. Minerva Med,2009.100(6):p.447-58.
21. Ytrebo, L.M., [Disturbances in ammonia metabolism in hepatic failure]. Tidsskr Nor Laegeforen,2007.127(11):p.1514-7.
22. Ytrebo, L.M., et al., Interorgan ammonia, glutamate, and glutamine trafficking in pigs with acute liver failure. Am J Physiol Gastrointest Liver Physiol,2006.291(3): p. G373-81.
23. Graham, T.E. and D.A. MacLean, Ammonia and amino acid metabolism in human skeletal muscle during exercise. Can J Physiol Pharmacol,1992.70(1):p.132-41.
24. Holubek, W.J., S. Kalman, and R.S. Hoffman, Acetaminophen-induced acute liver failure:results of a United States multicenter, prospective study. Hepatology,2006. 43(4):p.880; author reply 882.
25. Schmidt, L.E. and F.S. Larsen, Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure. Crit Care Med,2006.34(2):p.337-43.
26. O'Grady, J.G, Broadening the view of acetaminophen hepatotoxicity. Hepatology, 2005.42(6):p.1252-4.
27. Bailey, B., D.K. Amre, and P. Gaudreault, Fulminant hepatic failure secondary to acetaminophen poisoning:a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med,2003.31(1): p.299-305.
28. Chun, L.J., et al., Acetaminophen hepatotoxicity and acute liver failure. J Clin Gastroenterol,2009.43(4):p.342-9.
29. Lee, W.M., Acetaminophen-related acute liver failure in the United States. Hepatol Res,2008.38(s1The 6 Japan Society of Hepatology Single Topic Conference:Liver Failure:Recent Progress and Pathogenesis to Management.28-29 September 2007, Iwate, Japan):p. S3-S8.
30. Mour, G, et al., Acute renal dysfunction in acetaminophen poisoning. Ren Fail, 2005.27(4):p.381-3.
31. Cooper, S.C., et al., Outcomes of liver transplantation for paracetamol (acetaminophen)-induced hepatic failure. Liver Transpl,2009.15(10):p.1351-7.
32. Li, X.Y., et al., [A simple scoring system to evaluate the severity of acute-on-chronic liver failure in hepatitis B]. Zhonghua Yi Xue Za Zhi,2009.89(47):p.3353-5.
33. Ganem, D., Persistent infection of humans with hepatitis B virus:mechanisms and consequences. Rev Infect Dis,1982.4(5):p.1026-47.
34. McMahon, B.J., Natural history of chronic hepatitis B-clinical implications. Medscape J Med,2008.10(4):p.91.
35. Kumar, A., et al., Does co-infection with multiple viruses adversely influence the course and outcome of sporadic acute viral hepatitis in children? J Gastroenterol Hepatol,2006.21(10):p.1533-7.
36. Lusida, M.I., et al., Genotype and subtype analyses of hepatitis B virus (HBV) and possible co-infection of HBV and hepatitis C virus (HCV) or hepatitis D virus (HDV) in blood donors, patients with chronic liver disease and patients on hemodialysis in Surabaya, Indonesia. Microbiol Immunol,2003.47(12):p.969-75.
37. Tossing, G., Therapy of chronic hepatitis B and C and treatment options in HCV-HIV co-infection-European Conference on Infectious Diseases and Tropical Medicine, EuCID 2001,3-6 May 2001, Leipzig. Eur J Med Res,2001.6(6):p. 272-4.
38. Ghoshal, U.C., et al., Plasmodium falciparum and hepatitis E virus co-infection in fulminant hepatic failure. Indian J Gastroenterol,2001.20(3):p.111.
39. Jain, A., et al., Hepatitis C virus infection in sporadic fulminant viral hepatitis in North India:cause or co-factor? Eur J Gastroenterol Hepatol,1999.11(11):p. 1231-7.
1. Hirschhorn, J.N. and M.J. Daly, Genome-wide association studies for common diseases and complex traits. Nat Rev Genet,2005.6(2):p.95-108.
2. A haplotype map of the human genome. Nature,2005.437(7063):p.1299-320.
3. The International HapMap Project. Nature,2003.426(6968):p.789-96.
4. Frazer, K.A., et al., A second generation human haplotype map of over 3.1 million SNPs. Nature,2007.449(7164):p.851-61.
5. Hardy, J. and A. Singleton, Genomewide association studies and human disease. N Engl J Med,2009.360(17):p.1759-68.
6. Tregouet, D.A., et al., Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet,2009.41(3):p.283-5.
7. Samani, N.J., et al., Genomewide association analysis of coronary artery disease. N Engl J Med,2007.357(5):p.443-53.
8. Matarin, M., et al., A genome-wide genotyping study in patients with ischaemic stroke:initial analysis and data release. Lancet Neurol,2007.6(5):p.414-20.
9. Hanis, C.L., et al., A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet, 1996.13(2):p.161-6.
10. Cohen, J.C., et al., Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science,2004.305(5685):p.869-72.
11. Moffatt, M.F., et al., Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature,2007.448(7152):p.470-3.
12. Franke, A., et al., Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet.42(4):p.292-4.
13. Asslaber, D., et al., MicroRNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia. Blood.
14. Martin, M.M., et al., The human angiotensin Ⅱ type 1 receptor +1166 A/C polymorphism attenuates microrna-155 binding. J Biol Chem,2007.282(33):p. 24262-9.
15. Arisawa, T., et al., A polymorphism of microRNA 27a genome region is associated with the development of gastric mucosal atrophy in Japanese male subjects. Dig Dis Sci,2007.52(7):p.1691-7.
16. Saunders, M.A., H. Liang, and W.H. Li, Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci U S A,2007.104(9):p.3300-5.
17. Deng, G, et al., Regulatory polymorphisms in the promoter of CXCLIO gene and disease progression in male hepatitis B virus carriers. Gastroenterology,2008. 134(3):p.716-26.
2. Lok, A.S. and B.J. McMahon, Chronic hepatitis B. Hepatology,2007.45(2):p. 507-39.
3. Lok, A.S. and B.J. McMahon, Chronic hepatitis B:update 2009. Hepatology,2009. 50(3):p.661-2.
4. Ganem, D. and A.M. Prince, Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med,2004.350(11):p.1118-29.
5. McMahon, B.J., The natural history of chronic hepatitis B virus infection. Semin Liver Dis,2004.24 Suppl 1:p.17-21.
6. McMahon, B.J., Epidemiology and natural history of hepatitis B. Semin Liver Dis, 2005.25 Suppl 1:p.3-8.
7. McMahon, B.J., The natural history of chronic hepatitis B virus infection. Hepatology,2009.49(5 Suppl):p. S45-55.
8. Taylor, B.C., et al., Clinical outcomes in adults with chronic hepatitis B in association with patient and viral characteristics:A systematic review of evidence. Hepatology,2009.49(5 Suppl):p. S85-95.
9. Gandhi, M.J., et al., Hepatitis B virions isolated with antibodies to the pre-S1 domain reveal occult viremia by PCR in Alaska Native HBV carriers who have seroconverted. Transfusion,2000.40(8):p.910-6.
10. Liang, T.J., et al., Hepatitis B virus precore mutation and fulminant hepatitis in the United States. A polymerase chain reaction-based assay for the detection of specific mutation. J Clin Invest,1994.93(2):p.550-5.
11. Livingston, S.E., et al., Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology,2007.133(5):p. 1452-7.
12. McMahon, B.J., et al., A comprehensive programme to reduce the incidence of hepatitis B virus infection and its sequelae in Alaskan natives. Lancet,1987. 2(8568):p.1134-6.
13. Deng, G., et al., Regulatory polymorphisms in the promoter of CXCL10 gene and disease progression in male hepatitis B virus carriers. Gastroenterology,2008. 134(3):p.716-26.
14. Deng, G., et al., Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology,2004.40(2):p. 318-26.
15. Dong, X., et al., Association of DLC1 gene polymorphism with susceptibility to hepatocellular carcinoma in Chinese hepatitis B virus carriers. Cancer Epidemiol, 2009.33(3-4):p.265-70.
16. Kamatani, Y., 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):p.591-5.
17. Hirankarn, N., et al., Association of interleukin-18 gene polymorphism (-607A/A genotype) with susceptibility to chronic hepatitis B virus infection. Tissue Antigens, 2007.70(2):p.160-3.
18. Hohler, T., et al., A tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated with chronic hepatitis B infection. Clin Exp Immunol, 1998.111(3):p.579-82.
19. Kacprzak-Bergman, I. and J. Halasa, Polymorphism of the fourth component of complement (C4) and three clinical pictures of hepatitis B virus infection in children. Arch Immunol Ther Exp (Warsz),1997.45(4):p.295-300.
20. Lei, R.X., et al., Influence of a single nucleotide polymorphism in the P1 promoter of the furin gene on transcription activity and hepatitis B virus infection. Hepatology, 2009.50(3):p.763-71.
21. Park, J.S., et al., [Association of interleukin-12 gene polymorphism with persistence of hepatitis B virus infection and hepatocellular carcinoma]. Korean J Gastroenterol, 2007.50(5):p.313-8.
22. Ramezani, A., et al., Association of human leukocyte antigen polymorphism with outcomes of hepatitis B virus infection. J Gastroenterol Hepatol,2008.23(11):p. 1716-21.
23. Ribeiro, C.S., J.E. Visentainer, and R.A. Moliterno, Association of cytokine genetic polymorphism with hepatitis B infection evolution in adult patients. Mem Inst Oswaldo Cruz,2007.102(4):p.435-40.
24. Somi, M.H., et al., Tumor necrosis factor-alpha gene promoter polymorphism in Iranian patients with chronic hepatitis B. Indian J Gastroenterol,2006.25(1):p. 14-5.
25. The International HapMap Project. Nature,2003.426(6968):p.789-96.
26. A haplotype map of the human genome. Nature,2005.437(7063):p.1299-320.
27. Liu, L., et al., [Study of the quasispecies dynamics of serum hepatitis B virus in a patient with acute exacerbations of chronic hepatitis B]. Zhonghua Gan Zang Bing Za Zhi,2006.14(1):p.29-32.
28. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet,2009.41(7):p.824-8.
29. Barrett, J.C., et al., Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet,2009.
30. Barrett, J.C., et al., Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet,2008.40(8):p.955-62.
31. Xu, X., et al., DNA pooling analysis of 21 norepinephrine transporter gene SNPs with attention deficit hyperactivity disorder:no evidence for association. Am J Med Genet B Neuropsychiatr Genet,2005.134B(1):p.115-8.
32. Butcher, L.M., et al., Association analysis of mild mental impairment using DNA pooling to screen 432 brain-expressed single-nucleotide polymorphisms. Mol Psychiatry,2005.10(4):p.384-92.
33. Sham, P., et al., DNA Pooling:a tool for large-scale association studies. Nat Rev Genet,2002.3(11):p.862-71.
34. Barratt, B.J., et al., Identification of the sources of error in allele frequency estimations from pooled DNA indicates an optimal experimental design. Ann Hum Genet,2002.66(Pt 5-6):p.393-405.
35. Docherty, S.J., et al., Applicability of DNA pools on 500 K SNP microarrays for cost-effective initial screens in genomewide association studies. BMC Genomics, 2007.8:p.214.
36. Permutt, M.A., et al., Searching for type 2 diabetes genes on chromosome 20. Diabetes,2002.51 Suppl 3:p. S308-15.
37. Visscher, P.M. and S. Le Hellard, Simple method to analyze SNP-based association studies using DNA pools. Genet Epidemiol,2003.24(4):p.291-6.
38. Kirov, G, et al., A genome-wide association study in 574 schizophrenia trios using DNA pooling. Mol Psychiatry,2009.14(8):p.796-803.
39. Pearson, J.V., 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):p.126-39.
40. Fabris, C., et al., Gene polymorphism at the interleukin 6-174 G> C locus affects the outcome of chronic hepatitis B. J Infect,2009.59(2):p.144-5.
41. Hardie, D.R., J. Kannemeyer, and L.M. Stannard, DNA single strand conformation polymorphism identifies five defined strains of hepatitis B virus (HBV) during an outbreak of HBV infection in an oncology unit. J Med Virol,1996.49(1):p.49-54.
42. Yu, M.W., et al., A p53 genetic polymorphism as a modulator of hepatocellular carcinoma risk in relation to chronic liver disease, familial tendency, and cigarette smoking in hepatitis B carriers. Hepatology,1999.29(3):p.697-702.
43. Zhou, J., et al., A non-synonymous single nucleotide polymorphism in IFNAR1 affects susceptibility to chronic hepatitis B virus infection. J Viral Hepat,2009. 16(1):p.45-52.
44. Zhu, Z.Z., et al., A p53 polymorphism modifies the risk of hepatocellular carcinoma among non-carriers but not carriers of chronic hepatitis B virus infection. Cancer Lett,2005.229(1):p.77-83.
45. Skol, A.D., et al., Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet,2006.38(2):p.209-13.
46. Papassotiropoulos, A., et al., Common Kibra alleles are associated with human memory performance. Science,2006.314(5798):p.475-8.
47. Abdulla, M.A., et al., Mapping human genetic diversity in Asia. Science,2009. 326(5959):p.1541-5.
48. Xu, S., et al., Genomic dissection of population substructure of Han Chinese and its implication in association studies. Am J Hum Genet,2009.85(6):p.762-74.
49. Gu, J.W., et al., Long-term High Salt Diet Causes Hypertension and Decreases Renal Expression of Vascular Endothelial Growth Factor in Sprague-Dawley Rats. J Am Soc Hypertens,2008.2(4):p.275-85.
50. Koga, Y., et al., High salt intake enhances blood pressure increase during development of hypertension via oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats. Hypertens Res,2008.31(11):p.2075-83.
51. Mori, T., et al., High perfusion pressure accelerates renal injury in salt-sensitive hypertension. J Am Soc Nephrol,2008.19(8):p.1472-82.
52. Campese, V.M., et al., High salt intake inhibits nitric oxide synthase expression and aggravates hypertension in rats with chronic renal failure. J Nephrol,2002.15(4):p. 407-13.
53. Agarwal, M.M., et al., Gestational diabetes:fasting capillary glucose as a screening test in a multi-ethnic, high-risk population. Diabet Med,2009.26(8):p.760-5.
54. Cambuli, V.M., et al., Oral glucose tolerance test in Italian overweight/obese children and adolescents results in a very high prevalence of impaired fasting glycaemia, but not of diabetes. Diabetes Metab Res Rev,2009.25(6):p.528-34.
55. Ferland, A., et al., Impact of high-fat/low-carbohydrate, high-, low-glycaemic index or low-caloric meals on glucose regulation during aerobic exercise in Type 2 diabetes. Diabet Med,2009.26(6):p.589-95.
56. Modugno, F., et al., Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer. Int J Cancer,2006.118(5):p.1292-301.
57. Sasco, A.J., R. Kaaks, and R.E. Little, Breast cancer:occurrence, risk factors and hormone metabolism. Expert Rev Anticancer Ther,2003.3(4):p.546-62.
58. Bradlow, H.L., et al., Workshop on hormones, hormone metabolism, the environment, and breast cancer. J Natl Cancer Inst,1998.90(1):p.67.
59. Watanabe, M., et al., Congenital anomalies in a child born from a mother with interferon-treated chronic hepatitis B. Am J Gastroenterol,2001.96(5):p.1668-9.
60. Oren, H., O. Duzovali, and G Irken, Recombinant alpha-2a interferon treatment in a child with T-cell leukemia and chronic hepatitis B. Ann Hematol,1998.77(4):p. 187-90.
61. Basson, C.T., et al., Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet,1997.15(1):p.30-5.
62. Li, Q.Y., et al., Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet,1997.15(1):p.21-9.
63. Takeuchi, J.K., et al., Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis. Development,2003.130(24):p.5953-64.
64. Plageman, T.F., Jr. and K.E. Yutzey, Microarray analysis of Tbx5-induced genes expressed in the developing heart. Dev Dyn,2006.235(10):p.2868-80.
65. Goetz, S.C., D.D. Brown, and F.L. Conlon, TBX5 is required for embryonic cardiac cell cycle progression. Development,2006.133(13):p.2575-84.
66. Liberatore, C.M., R.D. Searcy-Schrick, and K.E. Yutzey, Ventricular expression of tbx5 inhibits normal heart chamber development. Dev Biol,2000.223(1):p. 169-80.
67. Maitra, M., et al., Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Dev Biol,2009.326(2):p.368-77.
68. Moskowitz, I.P., et al., A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development. Cell,2007.129(7):p. 1365-76.
69. Hiroi, Y., et al., Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet,2001.28(3):p.276-80.
70. Liu, C.X., et al., Association of TBX5 gene polymorphism with ventricular septal defect in the Chinese Han population. Chin Med J (Engl),2009.122(1):p.30-4.
71. Wu, B.T., et al., A novel secreted, cell-surface glycoprotein containing multiple epidermal growth factor-like repeats and one CUB domain is highly expressed in primary osteoblasts and bones. J Biol Chem,2004.279(36):p.37485-90.
72. Haworth, K., et al., Expression of the Scube3 epidermal growth factor-related gene during early embryonic development in the mouse. Gene Expr Patterns,2007.7(5): p.630-4.
1. Polson, J. and W.M. Lee, AASLD position paper:the management of acute liver failure. Hepatology,2005.41(5):p.1179-97.
2. Ostapowicz, G., et al., Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med,2002.137(12):p. 947-54.
3. McMahon, B.J., The natural history of chronic hepatitis B virus infection. Hepatology,2009.49(5 Suppl):p. S45-55.
4. Jalan, R. and R. Williams, Bio-artificial liver support for acute liver failure:should we be using it to treat patients? Transplantation,2002.73(2):p.165-6.
5. Girlanda, R., et al., Long-term outcome of immunosuppression withdrawal after liver transplantation. Transplant Proc,2005.37(4):p.1708-9.
6. Adam, R., et al., Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study. Lancet,2000.356(9230):p.621-7.
7. Williams, R., Changing clinical patterns in acute liver failure. J Hepatol,2003. 39(4):p.660-1.
8. O'Grady, J.G., et al., Early indicators of prognosis in fulminant hepatic failure. Gastroenterology,1989.97(2):p.439-45.
9. O'Grady, J.G., Pathogenesis of acute liver failure. Trop Gastroenterol,1996.17(4):p. 199-201.
10. Yu, J.W., et al., Prediction value of model for end-stage liver disease scoring system on prognosis in patients with acute-on-chronic hepatitis B liver failure after plasma exchange and lamivudine treatment. J Gastroenterol Hepatol,2008.23(8 Pt 1):p. 1242-9.
11. Yu, J.W., GQ. Wang, and S.C. Li, Prediction of the prognosis in patients with acute-on-chronic hepatitis using the MELD scoring system. J Gastroenterol Hepatol, 2006.21(10):p.1519-24.
12. Saigal, S., et al., Auxiliary partial orthotopic liver transplantation in acute liver failure due to hepatitis B. Transpl Int,2002.15(7):p.369-73.
13. Sun, Q.F., et al., Prediction of the prognosis of patients with acute-on-chronic hepatitis B liver failure using the model for end-stage liver disease scoring system and a novel logistic regression model. J Viral Hepat,2009.16(7):p.464-70.
14. Li, X.M., et al., Analyses of prognostic indices of chronic liver failure caused by hepatitis virus. World J Gastroenterol,2005.11(18):p.2841-3.
15. Schiodt, F.V., et al., Alpha-fetoprotein and prognosis in acute liver failure. Liver Transpl,2006.12(12):p.1776-81.
16. O'Grady, J.G, Fulminant hepatitis in patients with chronic liver disease. J Viral Hepat,2000.7 Suppl 1:p.9-10.
17. Dhiman, R.K., et al., Early indicators of prognosis in fulminant hepatic failure:an assessment of the Model for End-Stage Liver Disease (MELD) and King's College Hospital criteria. Liver Transpl,2007.13(6):p.814-21.
18. Anand, A.C., P. Nightingale, and J.M. Neuberger, Early indicators of prognosis in fulminant hepatic failure:an assessment of the King's criteria. J Hepatol,1997. 26(1):p.62-8.
19. Taylor, B.C., et al., Clinical outcomes in adults with chronic hepatitis B in association with patient and viral characteristics:A systematic review of evidence. Hepatology,2009.49(5 Suppl):p. S85-95.
20. Mauss, S., Therapy of chronic hepatitis B:new goals and new treatments. Minerva Med,2009.100(6):p.447-58.
21. Ytrebo, L.M., [Disturbances in ammonia metabolism in hepatic failure]. Tidsskr Nor Laegeforen,2007.127(11):p.1514-7.
22. Ytrebo, L.M., et al., Interorgan ammonia, glutamate, and glutamine trafficking in pigs with acute liver failure. Am J Physiol Gastrointest Liver Physiol,2006.291(3): p. G373-81.
23. Graham, T.E. and D.A. MacLean, Ammonia and amino acid metabolism in human skeletal muscle during exercise. Can J Physiol Pharmacol,1992.70(1):p.132-41.
24. Holubek, W.J., S. Kalman, and R.S. Hoffman, Acetaminophen-induced acute liver failure:results of a United States multicenter, prospective study. Hepatology,2006. 43(4):p.880; author reply 882.
25. Schmidt, L.E. and F.S. Larsen, Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure. Crit Care Med,2006.34(2):p.337-43.
26. O'Grady, J.G, Broadening the view of acetaminophen hepatotoxicity. Hepatology, 2005.42(6):p.1252-4.
27. Bailey, B., D.K. Amre, and P. Gaudreault, Fulminant hepatic failure secondary to acetaminophen poisoning:a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med,2003.31(1): p.299-305.
28. Chun, L.J., et al., Acetaminophen hepatotoxicity and acute liver failure. J Clin Gastroenterol,2009.43(4):p.342-9.
29. Lee, W.M., Acetaminophen-related acute liver failure in the United States. Hepatol Res,2008.38(s1The 6 Japan Society of Hepatology Single Topic Conference:Liver Failure:Recent Progress and Pathogenesis to Management.28-29 September 2007, Iwate, Japan):p. S3-S8.
30. Mour, G, et al., Acute renal dysfunction in acetaminophen poisoning. Ren Fail, 2005.27(4):p.381-3.
31. Cooper, S.C., et al., Outcomes of liver transplantation for paracetamol (acetaminophen)-induced hepatic failure. Liver Transpl,2009.15(10):p.1351-7.
32. Li, X.Y., et al., [A simple scoring system to evaluate the severity of acute-on-chronic liver failure in hepatitis B]. Zhonghua Yi Xue Za Zhi,2009.89(47):p.3353-5.
33. Ganem, D., Persistent infection of humans with hepatitis B virus:mechanisms and consequences. Rev Infect Dis,1982.4(5):p.1026-47.
34. McMahon, B.J., Natural history of chronic hepatitis B-clinical implications. Medscape J Med,2008.10(4):p.91.
35. Kumar, A., et al., Does co-infection with multiple viruses adversely influence the course and outcome of sporadic acute viral hepatitis in children? J Gastroenterol Hepatol,2006.21(10):p.1533-7.
36. Lusida, M.I., et al., Genotype and subtype analyses of hepatitis B virus (HBV) and possible co-infection of HBV and hepatitis C virus (HCV) or hepatitis D virus (HDV) in blood donors, patients with chronic liver disease and patients on hemodialysis in Surabaya, Indonesia. Microbiol Immunol,2003.47(12):p.969-75.
37. Tossing, G., Therapy of chronic hepatitis B and C and treatment options in HCV-HIV co-infection-European Conference on Infectious Diseases and Tropical Medicine, EuCID 2001,3-6 May 2001, Leipzig. Eur J Med Res,2001.6(6):p. 272-4.
38. Ghoshal, U.C., et al., Plasmodium falciparum and hepatitis E virus co-infection in fulminant hepatic failure. Indian J Gastroenterol,2001.20(3):p.111.
39. Jain, A., et al., Hepatitis C virus infection in sporadic fulminant viral hepatitis in North India:cause or co-factor? Eur J Gastroenterol Hepatol,1999.11(11):p. 1231-7.
1. Hirschhorn, J.N. and M.J. Daly, Genome-wide association studies for common diseases and complex traits. Nat Rev Genet,2005.6(2):p.95-108.
2. A haplotype map of the human genome. Nature,2005.437(7063):p.1299-320.
3. The International HapMap Project. Nature,2003.426(6968):p.789-96.
4. Frazer, K.A., et al., A second generation human haplotype map of over 3.1 million SNPs. Nature,2007.449(7164):p.851-61.
5. Hardy, J. and A. Singleton, Genomewide association studies and human disease. N Engl J Med,2009.360(17):p.1759-68.
6. Tregouet, D.A., et al., Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet,2009.41(3):p.283-5.
7. Samani, N.J., et al., Genomewide association analysis of coronary artery disease. N Engl J Med,2007.357(5):p.443-53.
8. Matarin, M., et al., A genome-wide genotyping study in patients with ischaemic stroke:initial analysis and data release. Lancet Neurol,2007.6(5):p.414-20.
9. Hanis, C.L., et al., A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet, 1996.13(2):p.161-6.
10. Cohen, J.C., et al., Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science,2004.305(5685):p.869-72.
11. Moffatt, M.F., et al., Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature,2007.448(7152):p.470-3.
12. Franke, A., et al., Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet.42(4):p.292-4.
13. Asslaber, D., et al., MicroRNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia. Blood.
14. Martin, M.M., et al., The human angiotensin Ⅱ type 1 receptor +1166 A/C polymorphism attenuates microrna-155 binding. J Biol Chem,2007.282(33):p. 24262-9.
15. Arisawa, T., et al., A polymorphism of microRNA 27a genome region is associated with the development of gastric mucosal atrophy in Japanese male subjects. Dig Dis Sci,2007.52(7):p.1691-7.
16. Saunders, M.A., H. Liang, and W.H. Li, Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci U S A,2007.104(9):p.3300-5.
17. Deng, G, et al., Regulatory polymorphisms in the promoter of CXCLIO gene and disease progression in male hepatitis B virus carriers. Gastroenterology,2008. 134(3):p.716-26.