Hong Zhang

Peking University, Peping, Beijing, China

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Publications (123)482.22 Total impact

  • 07/2015; DOI:10.1002/art.39268
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    ABSTRACT: Recently, common variants within or near ATG5, which is a key autophagy gene required for the formation of autophagosomes, have been identified as a candidate gene of systemic lupus erythematosus (SLE) by several genome-wide association studies. Moreover, elevated ATG5 expression was observed in SLE as well as other autoimmune diseases. However, no significant associations between variants within ATG5 and SLE were identified in several Chinese populations. The present study was conducted to further check the genetic role of ATG5 by associating both common and rare variants of ATG5 in Chinese patients with lupus nephritis (LN), a major phenotype with poor prognosis in SLE.To detect the association of common variants of ATG5 with LN, 7 tagging single nucleotide polymorphisms (SNPs) designed in immunochip and 4 SNPs reported to be associated with SLE were genotyped in 500 LN patients and 500 healthy controls. Furthermore, direct sequencing of exons and their flanking regions in 90 LN patients, 30 SLE patients, and 60 healthy controls were performed. Functional genomic annotation was performed by using public databases.None of the 11 tagging SNPs was observed to be associated with LN. By sequencing, 13 variants were identified, including 5 common SNPs, 7 not previously described, and 1 reported as rare variants (<1%) in the Single Nucleotide Polymorphism Database or the 1000 Genome project. None of the 5 common SNPs showed significant association between patients and controls, whereas increased frequencies of rare or novel variants were observed in patients compared with healthy controls, with 6/90 in LN patients, 2/30 in SLE patients, and 1/163 in healthy controls. Although these rare variants were observed to be located in the flanking regions of exons instead of missense mutations, patients carrying them tended to have severe clinical phenotype, and in silicon analysis suggested their regulatory effects.Increased frequencies of rare variants of ATG5 were identified in patients with LN and SLE compared with healthy controls, highlighting a likely important role of rare ATG5 variants in Chinese SLE patients.
    Medicine 06/2015; 94(22):e939. DOI:10.1097/MD.0000000000000939 · 4.87 Impact Factor
  • Xu-Jie Zhou, Hong Zhang
    Rheumatology (Oxford, England) 05/2015; DOI:10.1093/rheumatology/kev118 · 4.44 Impact Factor
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    ABSTRACT: Familial renal glucosuria (FRG) is characterized by persistent glucosuria despite normal serum glucose and the absence of overt tubular dysfunction. Variants in solute carrier family 5 (sodium-glucose co-transporter), member 2 (SLC5A2) have been reported in FRG patients. However, the functional and expression-related consequences of such variants have been scarcely investigated. In the current study, we studied five FRG families and identified six missense mutations, including four novel variants (c.1051T>C/p.(C351R), c.1400T>C/p.(V467A), c.1420G>C/p.(A474P), c.1691G>A/p.(R564Q); RNA not analyzed) and two variants that had been previously reported (c.294C>A/p.(F98L), c.736C>T/p.(P246S); RNA not analyzed). The probands were either heterozygous or compound heterozygous for SLC5A2 variants and had glucosuria of 5.9–19.6 g/day. Human 293 cells were transfected with plasmid constructs to study the expression and function of SLC5A2 Variants in vitro. Western blotting revealed that the expression levels of SLC5A2–351R-GFP, SLC5A2–467A-GFP, SLC5A2–474P-GFP and SLC5A2–564Q-GFP were significantly decreased compared with wild-type SLC5A2-GFP (37–55%). Confocal microscopy revealed that three variants (c.1400T>C, c.1420G>C, c.1691G>A) resulted in a loss of the punctate membrane pattern typical of wild-type SLC5A2. All Variants had a significantly lower transport capacity in than the wild-type control. The current study provides a starting point to further investigate the molecular mechanism of SLC5A2 in FRG families and provides functional clues for anti-diabetes drugs.This article is protected by copyright. All rights reserved
    Human Mutation 01/2015; 36(1). DOI:10.1002/humu.22714 · 5.05 Impact Factor
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    ABSTRACT: Abstract We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.
    Nature Genetics 10/2014; DOI:10.1038/ng.3118 · 29.65 Impact Factor
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    ABSTRACT: Objective Several novel susceptibility genes for systemic lupus erythematosus (SLE) and IgA nephropathy have been identified in recent genome-wide association studies. Since both lupus nephritis and IgA nephropathy are autoimmune diseases of the kidney, they may share common disease mechanisms that overlap with genetic susceptibility. To test this hypothesis, we sought to identify genetic variants associated with IgA nephropathy in lupus nephritis. Methods In the first stage, 500 patients with lupus nephritis, 240 SLE patients without nephritis, and 500 healthy controls were enrolled. Fifteen single-nucleotide polymorphisms (SNPs) that had the topmost association signals with IgA nephropathy were selected for further testing in patients with lupus nephritis. Three independent cohorts from Beijing, Shanghai, and Hong Kong were included as replicates. We also analyzed the functional significance of identified noncoding variants on regulatory motifs and gene expression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. ResultsIn addition to associations with HLA gene polymorphisms, genetic variants of MTMR3 in 22q12 showed associations with lupus nephritis (for rs9983A, OR 1.61 [95% CI 1.19-2.19], P = 2.07 x 10(-3)) compared to healthy controls in the first stage. Associations were replicated and reinforced among northern Han Chinese (for lupus nephritis patients versus SLE patients without nephritis, P = 0.01) but not southern Han Chinese, although significant genetic heterogeneity was observed. Conservative and regulatory features of rs9983 were predicted in in silico analyses. In expression analysis, we observed lower MTMR3 transcription levels in samples of blood with rs9983A and in renal biopsy samples from lupus nephritis and IgA nephropathy patients. Conclusion Our results suggest that the MTMR3 gene is shared between IgA nephropathy and lupus nephritis in the northern Chinese population, further highlighting the role of autophagy in SLE. However, widespread replication of these experiments, fine mapping, and functional assays are required to establish this connection.
    10/2014; 66(10). DOI:10.1002/art.38749
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    ABSTRACT: Complement activation is common in patients with IgA nephropathy (IgAN) and associated with disease severity. Our recent genome-wide association study of IgAN identified susceptibility loci on 1q23 containing the complement regulatory protein-encoding genes CFH and CFHR1-5, with rs6677604 in CFH as the top single-nucleotide polymorphism and CFHR3-1 deletion (CFHR3-1∆) as the top signal for copy number variation. In this study, to explore the clinical effects of variation in CFH, CFHR3, and CFHR1 on IgAN susceptibility and progression, we enrolled two populations. Group 1 included 1178 subjects with IgAN and available genome-wide association study data. Group 2 included 365 subjects with IgAN and available clinical follow-up data. In group 1, rs6677604 was associated with mesangial C3 deposition by genotype-phenotype correlation analysis. In group 2, we detected a linkage between the rs6677604-A allele and CFHR3-1∆ and found that the rs6677604-A allele was associated with higher serum levels of CFH and lower levels of the complement activation split product C3a. Furthermore, CFH levels were positively associated with circulating C3 levels and negatively associated with mesangial C3 deposition. Moreover, serum levels of the pathogenic galactose-deficient glycoform of IgA1 were also associated with the degree of mesangial C3 deposition in patients with IgAN. Our findings suggest that genetic variants in CFH, CFHR3, and CFHR1 affect complement activation and thereby, predispose patients to develop IgAN.
    Journal of the American Society of Nephrology 09/2014; 26(5). DOI:10.1681/ASN.2014010096 · 9.47 Impact Factor
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    ABSTRACT: The cingulum and fornix play an important role in memory, attention, spatial orientation, and feeling functions. Both microstructure and length of these limbic tracts can be affected by mental disorders such as Alzheimer's disease, depression, autism, anxiety, and schizophrenia. To date, there has been little systematic characterization of their microstructure, length, and functional connectivity in normally developing brains. In this study, diffusion tensor imaging (DTI) and resting state functional MRI (rs-fMRI) data from 65 normally developing right-handed subjects from birth to young adulthood was acquired. After cingulate gyrus part of the cingulum (cgc), hippocampal part of the cingulum (cgh) and fornix (fx) were traced with DTI tractography, absolute and normalized tract lengths and DTI-derived metrics including fractional anisotropy, mean, axial, and radial diffusivity were measured for traced limbic tracts. Free water elimination (FWE) algorithm was adopted to improve accuracy of the measurements of DTI-derived metrics. The role of these limbic tracts in the functional network at birth and adulthood was explored. We found a logarithmic age-dependent trajectory for FWE-corrected DTI metric changes with fast increase of microstructural integrity from birth to 2 years old followed by a slow increase to 25 years old. Normalized tract length of cgc increases with age, while no significant relationship with age was found for normalized tract lengths of cgh and fx. Stronger microstructural integrity on the left side compared to that of the right side was found. With integrated DTI and rs-fMRI, the key connectional role of cgc and cgh in the default mode network was confirmed as early as birth. Systematic characterization of length and DTI metrics after FWE correction of limbic tracts offers insight into their morphological and microstructural developmental trajectories. These trajectories may serve as a normal reference for pediatric patients with mental disorders.
    Frontiers in Aging Neuroscience 08/2014; 6:228. DOI:10.3389/fnagi.2014.00228 · 2.84 Impact Factor
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    ABSTRACT: Objective Human neutrophil peptides (HNP) were recently implicated in the neutrophil extracellular trap (NET) complex, the impaired degradation of which has been associated with lupus nephritis (LN).Methods Forty LN patients, 40 SLE patients without kidney injury, 63 immunoglobulin A nephropathy (IgAN) patients, 20 minimal change disease (MCD) patients and 33 healthy controls were included in the present study. LN, IgAN and MCD patients were diagnosed with renal biopsy. LN patients were followed for a median period of 5.5 years. Clinical and laboratory data at the time of renal biopsy and follow-up were collected for each LN patient. Serum levels of HNP1–3 were measured with enzyme-linked immunosorbent assay.ResultsSerum HNP1-3 levels in LN patients were significantly higher than for SLE patients without kidney injury (P < 0.001), IgAN patients (P = 0.012), MCD patients (P = 0.010) and healthy controls (P = 0.022). Serum HNP1–3 levels were an independent indicator of LN (P = 0.006, OR = 7.5, 95% CI, 1.782–31.842), were statistically correlated with urinary protein excretion (P = 0.009) and activity index (P = 0.042) and were only marginally correlated with neutrophils (P = 0.054) and white blood cell counts (P = 0.051). Serum levels of HNP1–3 were a predictor of proteinuria remission after correction for multiple parameters (multivariate hazard 0.209; 95% CI 0.046–0.951; P = 0.043).Conclusions The data from this study indicated that HNP1–3, one component of the NET, is a potential biomarker for LN.
    International Journal of Rheumatic Diseases 08/2014; 18(5). DOI:10.1111/1756-185X.12433 · 1.77 Impact Factor
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    ABSTRACT: Background Endothelial injury, which may present clinically as hypertension, proteinuria and increased von Willebrand Factor (vWF) level, is a common manifestation in IgA nephropathy (IgAN). However, causal factors for endothelial injury in IgAN are not completely understood. An imbalance of vascular endothelial growth factor/Soluble fms-like tyrosine kinase-1 (VEGF/sFlt-1) has been observed in many diseases with endothelial dysfunction, including pre-eclampsia and diabetic retinopathy, but whether it contributes to endothelial injury in IgAN requires further exploration. Methods Initially, 96 IgAN patients and 22 healthy volunteers were enrolled as a discovery cohort. VEGF/sFlt-1, sFlt-1 and VEGF levels were compared between patients with IgAN and healthy volunteers to explore the underlying factors that contribute to endothelial injury in IgAN. The identified contributor (sFlt-1) was further confirmed in a replication cohort, which included 109 IgAN patients and 30 healthy volunteers. Correlations of sFlt-1 with hypertension, proteinuria, Oxford-E score and plasma vWF were further evaluated in the combined 205 patients with IgAN. Results VEGF/sFlt-1 levels were significantly lower in IgAN patients than healthy volunteers (0.33±0.27 vs. 0.43±0.22, p = 0.02) in the discovery cohort. Within the ratio, plasma sFlt-1 levels were significantly elevated (101.18±25.19 vs. 79.73±18.85 pg/ml, p<0.001), but plasma VEGF levels showed no significant differences. Elevated sFlt-1 levels in the replication cohort were confirmed in IgAN patients (93.40±39.78 vs. 71.92±15.78 pg/ml, p<0.001). Plasma sFlt-1 levels in IgAN patients correlated with proteinuria (severe (>3.5 g/d) vs. moderate (1–3.5 g/d) vs. mild (<1 g/d) proteinuria: 115.95±39.09 vs. 99.89±28.55 vs. 83.24±33.92 pg/ml; severe vs. mild: p<0.001, moderate vs. mild p = 0.001, severe vs. moderate: p = 0.014), hypertension (with vs. without hypertension: 107.87±31.94 vs. 87.32±32.76 pg/ml, p = 0.015) and vWF levels (r = 0.161, p = 0.021). Conclusions The present study found elevated sFlt-1 in IgAN patients and further identified its correlation with proteinuria, hypertension and vWF levels. These results suggested that elevated sFlt-1 contributes to endothelial injury in IgAN.
    PLoS ONE 07/2014; 9(7):e101779. DOI:10.1371/journal.pone.0101779 · 3.53 Impact Factor
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    ABSTRACT: Purpose: NAT10 (N-acetyltransferase 10) is a nucleolar protein, but may show subcellular redistribution in colorectal carcinoma (CRC). In this study, we evaluated membranous staining of NAT10 in colorectal carcinoma and its clinical implications, and explored the mechanism of regulation of NAT10 redistribution. Experimental Design: The expression and subcellular redistribution of NAT10, β-catenin, E-cadherin, GSK-3β were evaluated by immunohistochemistry in 222 cases of colorectal carcinoma. Regulation of NAT10 and its influence on cell motility were analyzed with inhibitors of GSK-3β, transfection of wild-type or kinase-inactivated GSK-3β, or expression of various domains of NAT10, and evaluated with immunofluorescence, Western blotting, and Trans-well assays. Results: NAT10 localized mainly in the nucleoli of normal tissues, and was redistributed to the membrane in cancer cells, particularly at the invasive "leading edge" of the tumor. This correlated well with nuclear accumulation of β-catenin (p<0.001). In addition, NAT10 membrane staining reflected depth of invasion and tendency to metastasize (all P values <0.001), and was associated with poorer prognosis (P=0.023). Evaluation of the mechanism involved demonstrated that subcellular redistribution of NAT10 may result from its increased stability and nuclear export, which is brought about by inhibition of GSK-3β. Moreover, redistribution of NAT10 induces alteration of cytoskeletal dynamics and increases cancer cell motility. Conclusions: The subcellular redistribution of NAT10 can be induced by decreases in GSK-3β activity. This redistribution increases cancer cell motility, and is thus correlated with invasive potential and poorer clinical outcome. This suggests NAT10 may be a useful prognostic marker and potential therapeutic target in CRC.
    Clinical Cancer Research 06/2014; 20(17). DOI:10.1158/1078-0432.CCR-13-3477 · 8.19 Impact Factor
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    ABSTRACT: The airway epithelium is exposed to a range of irritants in the environment that are known to trigger inflammatory response such as asthma. Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable cation channel critical for detecting noxious stimuli by sensory neurons. Recently increasing evidence suggests TRPV1 is also crucially involved in the pathophysiology of asthma on airway epithelium in human. Here we report that in airway epithelial cells TRPV1 activation potently induces allergic cytokine thymic stromal lymphopoietin (TSLP) release. TSLP induction by protease-activated receptor (PAR)-2 activation is also partially mediated by TRPV1 channels.
    FEBS Letters 06/2014; 588(17). DOI:10.1016/j.febslet.2014.06.018 · 3.34 Impact Factor
  • International Urology and Nephrology 06/2014; 46(11). DOI:10.1007/s11255-014-0755-5 · 1.29 Impact Factor
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    ABSTRACT: The effect of genetic markers associated with IgA nephropathy on risk of disease in sub-phenotype and progression is uncertain. Data from 2096 Chinese patients were used to create both un-weighted (uw) and weighted (w) genetic risk score (GRS). The association between GRS with disease susceptibility and clinical parameters were assessed. All nine selected single nucleotide polymorphisms (SNPs) were associated with susceptibility to IgAN. uwGRS and wGRS showed a similar fit in disease associations. With every 1-unit increase in the uwGRS, the disease risk increased by approximately 20%; whereas every one standard deviation increase in the wGRS, disease risk increased by approximately 40% ~ 60%. Association between rs3803800 and serum IgA was replicated, and risk groups in GRSs were associated with increased IgA/IgA1 levels. uwGRS9 ≥ 16 was an independent predictor for end stage renal disease (ESRD) in IgAN, with a relative risk of 2.52 (p = 6.68 × 10(-3)). In conclusion, we observed that GRSs comprising nine SNPs identified in a GWAS of IgAN were strongly associated with susceptibility to IgAN. The high risk GRS9 group had a high risk of ESRD in follow-up.
    Scientific Reports 05/2014; 4:4904. DOI:10.1038/srep04904 · 5.58 Impact Factor
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    ABSTRACT: Centrosome amplification which is a characteristic of cancer cells, has been understood as a driving force of genetic instability in the development of cancer. In previous work, we demonstrated that TEIF (transcriptional elements-interacting factor) distributes in the centrosomes and regulates centrosome status under both physiologic and pathologic conditions. Here we identify TEIF as a downstream effector in EGF/PI3K/Akt signaling. The addition of EGF or transfection of active Akt stimulates centrosome TEIF distribution, resulting in an increase of centrosome splitting and amplification, while inhibitors of either PI3K or Akt attenuate these changes in TEIF and the associated centrosome status. A consensus motif for Akt phosphorylation (RHRVLT) proved to be involved in centrosomal TEIF localization, and the 469-threonine of this motif may be phosphorylated by Akt both in vitro and in vivo. Elimination of this phosphorylated site on TEIF caused reduced centrosome distribution and centrosome splitting or amplification. Moreover, TEIF closely co-localized with C-NAP1 at the proximal ends of centrioles, and centriolar loading of TEIF stimulated by EGF/Akt could displace C-NAP1, resulting in centrosome splitting. These findings reveal linkage of the EGF/PI3K/Akt signaling pathway to regulation of centrosome status which may act as an oncogenic pathway and induce genetic instability in carcinogenesis.
    Biochimica et Biophysica Acta 04/2014; 1843(9). DOI:10.1016/j.bbamcr.2014.04.021 · 4.66 Impact Factor
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    Xu-Jie Zhou, Ming-Hui Zhao, Hong Zhang
    Rheumatology (Oxford, England) 04/2014; 53(9). DOI:10.1093/rheumatology/keu152 · 4.44 Impact Factor
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    ABSTRACT: Abstract Objectives: Recent animal experiments showed that CCR5-deficient lupus mice (CCR5(-/-)) were closely associated with aggravated lupus nephritis. CCR5 Δ32 variation, a nonsynonymous mutation of CCR5, resulted in altered CCR5 function. However, the CCR5 Δ32 mutation in human lupus nephritis has been rarely reported in the literature. Methods: A large case-control study that included 2010 samples from a Chinese population was conducted, followed by a meta-analysis combining the current and previously published studies to explore the effect of CCR5 Δ32 on lupus nephritis susceptibility. Results: Four CCR5 Δ32 heterozygote carriers were detected in lupus nephritis patients only. We detected no CCR5 Δ32 homozygotes in our study population. In the meta-analysis, including 1,092 cases and 2,229 controls, we found great heterogeneity between studies (p < 0.001, I(2)( )= 89.6%). Furthermore, stratified and sensitivity analyses suggested that ethnicity and CCR5 Δ32 allele frequency were the main origin of heterogeneity. In the subgroups without obvious heterogeneity, we observed a positive correlation between CCR5 Δ32 and lupus nephritis risk (p < 0.05). Conclusions: Our study confirmed that the CCR5 Δ32 mutation is a very rare variation found in the Chinese population with Han ethnicity. However, CCR5 Δ32 might play a role in lupus nephritis susceptibility. Future replications and functional studies are needed.
    Autoimmunity 04/2014; DOI:10.3109/08916934.2014.906581 · 2.75 Impact Factor
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    ABSTRACT: Bmi1 has been identified as an important regulator in breast cancer, but its relationship with other signaling molecules such as ERalpha and HER2 is undetermined. The expression of Bmi1 and its correlation with ERalpha, PR, Ki-67, HER2, p16INK4a, cyclin D1 and pRB was evaluated by immunohistochemistry in a collection of 92 cases of breast cancer and statistically analyzed. Stimulation of Bmi1 expression by ERalpha or 17beta-estradiol (E2) was analyzed in cell lines including MCF-7, MDA-MB-231, ERalpha-restored MDA-MB-231 and ERalpha-knockdown MCF-7 cells. Luciferase reporter and chromatin immunoprecipitation assays were also performed. Immunostaining revealed strong correlation of Bmi1 and ERalpha expression status in breast cancer. Expression of Bmi1 was stimulated by 17beta-estradiol in ERalpha-positive MCF-7 cells but not in ERalpha-negative MDA-MB-231 cells, while the expression of Bmi1 did not alter expression of ERalpha. As expected, stimulation of Bmi1 expression could also be achieved in ERalpha-restored MDA-MB-231 cells, and at the same time depletion of ERalpha decreased expression of Bmi1. The proximal promoter region of Bmi1 was transcriptionally activated with co-transfection of ERalpha in luciferase assays, and the interaction of the Bmi1 promoter with ERalpha was confirmed by chromatin immunoprecipitation. Moreover, in breast cancer tissues activation of the ERalpha-coupled Bmi1 pathway generally correlated with high levels of cyclin D1, while loss of its activity resulted in aberrant expression of p16INK4a and a high Ki-67 index, which implied a more aggressive phenotype of breast cancer. Expression of Bmi1 is influenced by ERalpha, and the activity of the ERalpha-coupled Bmi1 signature impacts p16INK4a and cyclin D1 status and thus correlates with the tumor molecular subtype and biologic behavior. This demonstrates the important role which is played by ERalpha-coupled Bmi1 in human breast cancer.
    BMC Cancer 02/2014; 14(1):122. DOI:10.1186/1471-2407-14-122 · 3.32 Impact Factor
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    Xu-Jie Zhou, Fa-Juan Cheng, Hong Zhang
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    ABSTRACT: Aberrations of both innate immunity and adaptive immunity in genetically predisposed individuals evoked by environmental factors are suggested to be implicated in pathophysiological processes of systemic lupus erythematosus (SLE). Autophagy, a degradation pathway in which cytoplasmic content is engulfed and degraded by the lysosome, has been recently demonstrated to be involved in multiple cytoplasmic homeostatic progresses and interact with nearly all parts of the innate and adaptive immune system. More recently, some lines of evidence from genetic, cell biology and model animal studies also suggests a pivotal role of autophagy in mediating the occurrence and development of SLE. We discuss and synthesize studies that have begun to demonstrate how autophagy cause and/or promote autoimmunity in SLE.
    International Reviews Of Immunology 02/2014; 34(3). DOI:10.3109/08830185.2013.879711 · 5.28 Impact Factor
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    ABSTRACT: One hypothesis states that IgA nephropathy (IgAN) is a syndrome with an autoimmune component. Recent studies strongly support the notion of shared genetics between immune-related diseases. This study investigated single-nucleotide polymorphisms (SNPs) reported to be associated with systemic lupus erythematosus (SLE) in a Chinese cohort of patients with IgAN and in controls. This study investigated whether SNP markers that had been reported to be associated with SLE were also associated with IgAN in a Chinese population. The study cohort consisted of 1194 patients with IgAN and 902 controls enrolled in Peking University First Hospital from 1997 to 2008. Ninety-six SNPs mapping to 60 SLE loci with reported P values <1×10(-5) were investigated. CFH (P=8.41×10(-6)), HLA-DRA (P=4.91×10(-6)), HLA-DRB1 (P=9.46×10(-9)), PXK (P=3.62×10(-4)), BLK (P=9.32×10(-3)), and UBE2L3 (P=4.07×10(-3)) were identified as shared genes between IgAN and SLE. All associations reported herein were corroborated by associations at neighboring SNPs. Many of the alleles that are risk alleles for SLE are protective alleles for IgAN. By analyses of two open independent expression quantitative trait loci (eQTL) databases, correlations between genotypes and corresponding gene expression were observed (P<0.05 in multiple populations), suggesting a cis-eQTL effect. From gene-expression databases, differential expressions of these genes were observed in IgAN. Additive interactions between PXK rs6445961and HLA-DRA rs9501626 (P=1.51×10(-2)), as well as multiplicative interactions between CFH rs6677604 and HLA-DRB1 rs9271366 (P=1.77×10(-2)), and between HLA-DRA rs9501626 and HLA-DRB1 rs9271366 (P=3.23×10(-2)) were observed. Disease risk decreased with accumulation of protective alleles. Network analyses highlighted four pathways: MHC class II antigen presentation, complement regulation, signaling by the B-cell receptor, and ubiquitin/proteasome-dependent degradation. From this "systems genetics" perspective, these data provide important clues for future studies on pleiotropy in IgAN and lupus nephritis.
    Clinical Journal of the American Society of Nephrology 01/2014; 9(4). DOI:10.2215/CJN.01860213 · 5.25 Impact Factor

Publication Stats

2k Citations
482.22 Total Impact Points

Institutions

  • 2003–2015
    • Peking University
      • Institute of Urology
      Peping, Beijing, China
  • 2014
    • Beijing Zoo
      Peping, Beijing, China
  • 2013–2014
    • Peking University Health Science Center
      Peping, Beijing, China
  • 2002–2013
    • Beijing Medical University
      • • Department of Medicine
      • • Institute of Nephrology
      • • Department of Internal Medicine
      Peping, Beijing, China
  • 2008–2012
    • Anhui Medical University
      • Department of Pathology
      Luchow, Anhui Sheng, China
  • 2000–2002
    • Okayama University
      • Department of Medicine and Clinical Science
      Okayama, Okayama, Japan