Rare inborn errors associated with chronic hepatitis B virus infection

Zhao, Qiang; Peng, Liang; Huang, Weijun; Li, Qibin; Pei, Yuanyuan; Yuan, Ping; Zheng, Lingyan; Zhang, Yongling; Deng, Jia; Zhong, Cheng; Hu, Bin; Ding, Hu; Wei, Fang; Li, Ru; Liao, Qijun; Chen, Lin; Deng, Weiping; Yan, Huijun; Hou, Jinghui; Wu, Qian; Xu, Tingting; Liu, Jinsong; Hu, Lirong; Peng, Tao; Chen, Suqing; Lai, Kar Neng; Yuen, Man Fung; Wang, Yue; Maini, Mala K.; Li, Caixia; Li, Miaoxin; Wang, Jian; Zhang, Xiuqing; Sham, Pak C.; Wang, Jun; Gao, Zhi; Wang, Yiming

doi:10.1002/hep.25850

Cited by 24 publications

(24 citation statements)

References 23 publications

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“…The human TMEM2 p.Ser1254Asn polymorphism is strongly associated with chronic hepatitis B virus infection in Chinese populations (odds ratio, 2.45; 95% confidence interval, 1.89 to 3.16; P=8.7210 212 ). 26 Exosomes have a role in hepatitis B infection, where they are involved in transmitting an IFN-a signal between nonpermissive liver nonparenchymal cells to permissive hepatocytes. 27 It may well be that TMEM2 is present on IFN-a-induced exosomes and is involved in their transmission.…”

Section: Discussionmentioning

confidence: 99%

Identification of Biomarkers for PKD1 Using Urinary Exosomes

Hogan

Bakeberg

Gainullin

et al. 2015

Journal of the American Society of Nephrology

113

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Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of ESRD. Affected individuals inherit a defective copy of either PKD1 or PKD2, which encode polycystin-1 (PC1) or polycystin-2 (PC2), respectively. PC1 and PC2 are secreted on urinary exosome-like vesicles (ELVs) (100-nm diameter vesicles), in which PC1 is present in a cleaved form and may be complexed with PC2. Here, label-free quantitative proteomic studies of urine ELVs in an initial discovery cohort (13 individuals with PKD1 mutations and 18 normal controls) revealed that of 2008 ELV proteins, 9 (0.32%) were expressed at significantly different levels in samples from individuals with PKD1 mutations compared to controls (P,0.03). In samples from individuals with PKD1 mutations, levels of PC1 and PC2 were reduced to 54% (P,0.02) and 53% (P,0.001), respectively. Transmembrane protein 2 (TMEM2), a protein with homology to fibrocystin, was 2.1-fold higher in individuals with PKD1 mutations (P,0.03). The PC1/TMEM2 ratio correlated inversely with height-adjusted total kidney volume in the discovery cohort, and the ratio of PC1/TMEM2 or PC2/TMEM2 could be used to distinguish individuals with PKD1 mutations from controls in a confirmation cohort. In summary, results of this study suggest that a test measuring the urine exosomal PC1/TMEM2 or PC2/TMEM2 ratio may have utility in diagnosis and monitoring of polycystic kidney disease. Future studies will focus on increasing sample size and confirming these studies. The data were deposited in the ProteomeXchange (identifier PXD001075).

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Section: Discussionmentioning

confidence: 99%

Identification of Biomarkers for PKD1 Using Urinary Exosomes

Hogan

Bakeberg

Gainullin

et al. 2015

Journal of the American Society of Nephrology

113

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“…We recruited 1865 healthy individuals in the same period and from the same city. The new recruits included 354 patients and 259 controls in addition to the 1603 patients and 1606 controls who were also included in the previously reported cohort and recruited by the same criteria (DNA from the rest of the individuals in the previously reported cohort had run out). All participants were of Chinese Han ethnicity.…”

Section: Methodsmentioning

confidence: 99%

The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B

Peng

Zhao

Li³

et al. 2015

Hepatology

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In the past 50 years there have been considerable efforts to identify the cellular receptor of hepatitis B virus (HBV). Recently, in vitro evidence from several groups has shown that the sodium-taurocholate cotransporting polypeptide (NTCP, which is encoded by SLC10A1 and transports bile acids into hepatic cells in enterohepatic recirculation) is a strong candidate. In particular, in vitro the p.Ser267Phe variation of SLC10A1 results in loss of HBV receptor function. We tested the role of NTCP as a receptor for HBV in chronic hepatitis B patients using a genetic association study. We selected SLC10A1 variants from 189 exomes. We used Sanger sequencing to follow up the association of the various SLC10A1 variants in a Han Chinese cohort of 1899 chronic hepatitis B patients and 1828 healthy controls. We further investigated the potential impact of the p.Ser267-Phe variant on NTCP function using structural analysis. The p.Ser267Phe variant was associated with healthy status (P 5 5.7 3 10 223 , odds ratio 5 0.36) irrespective of hepatitis B virus surface antibody status (P 5 6.2 3 10 221 and 1.5 3 10 210 , respectively, when the cases were compared with hepatitis B virus surface antibody-positive and -negative controls). The variation was also associated with a lower incidence of acute-on-chronic liver failure (P 5 0.007). The estimated heritability explained by this single variation was 3.2%. The population prevented fraction was around 13.0% among the southern Chinese. Our structural modeling showed that the p.Ser267Phe variant might interfere with ligand binding, thereby preventing HBV from cellular entry. Conclusion: The p.Ser267Phe NTCP variant is significantly associated with resistance to chronic hepatitis B and a lower incidence of acute-on-chronic liver failure. Our results support that NTCP is a cellular receptor for HBV in human infection. (HEPATOLOGY 2015;61:1251-1260 C hronic hepatitis B (CHB) affects approximately 240 million people worldwide and is responsible for about 780,000 deaths annually (http://www.who.int/mediacentre/factsheets/fs204/en/).Clinically, CHB holds the most significant medical consequences among hepatitis B virus (HBV)-infected individuals. Acute-on-chronic liver failure (ACLF) is the most urgent and lethal condition related to CHB.Abbreviations: ACLF, acute-on-chronic liver failure; AIM, ancestry-informative marker; ASBT, apical sodium-dependent bile acid transporter; CHB, chronic hepatitis B; HBV, hepatitis B virus; HBsAb, hepatitis B virus surface antibody; HBsAg, hepatitis B virus surface antigen; HDV, hepatitis D virus; NTCP, sodiumtaurocholate cotransporting polypeptide..From the

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“…Zhao et al recently associated a missense mutation in the LRR of NLRX1 with susceptibility to chronic hepatitis B infection in human patients. The replacement of the highly conserved Arg707 with a cysteine between a α helix and a β strand was hypothesized to interfere with the electrostatic potential of the region and consequently modulate the activity of the protein (220). Lastly, a group characterizing the molecular signature of SIV-induced gastrointestinal dysfunction found an increase in NLRX1 expression in rhesus macaques 90 days following SIV infection (221).…”

Section: Non-inflammasome-forming Nlrsmentioning

confidence: 99%

Functions of NOD-Like Receptors in Human Diseases

Zhong¹,

Kinio²,

Saleh³

2013

Front. Immunol.

267

215

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Nucleotide-binding and oligomerization domain NOD-like receptors (NLRs) are highly conserved cytosolic pattern recognition receptors that perform critical functions in surveying the intracellular environment for the presence of infection, noxious substances, and metabolic perturbations. Sensing of these danger signals by NLRs leads to their oligomerization into large macromolecular scaffolds and the rapid deployment of effector signaling cascades to restore homeostasis. While some NLRs operate by recruiting and activating inflammatory caspases into inflammasomes, others trigger inflammation via alternative routes including the nuclear factor-κB, mitogen-activated protein kinase, and regulatory factor pathways. The critical role of NLRs in development and physiology is demonstrated by their clear implications in human diseases. Mutations in the genes encoding NLRP3 or NLRP12 lead to hereditary periodic fever syndromes, while mutations in CARD15 that encodes NOD2 are linked to Crohn’s disease or Blau’s syndrome. Genome-wide association studies (GWASs) have identified a number of risk alleles encompassing NLR genes in a host of diseases including allergic rhinitis, multiple sclerosis, inflammatory bowel disease, asthma, multi-bacillary leprosy, vitiligo, early-onset menopause, and bone density loss in elderly women. Animal models have allowed the characterization of underlying effector mechanisms in a number of cases. In this review, we highlight the functions of NLRs in health and disease and discuss how the characterization of their molecular mechanisms provides new insights into therapeutic strategies for the management of inflammatory pathologies.

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Rare inborn errors associated with chronic hepatitis B virus infection

Cited by 24 publications

References 23 publications

Identification of Biomarkers for PKD1 Using Urinary Exosomes

Identification of Biomarkers for PKD1 Using Urinary Exosomes

The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B

Functions of NOD-Like Receptors in Human Diseases

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