Abstract:
BACKGROUND:IgA nephropathy (IgAN) is a common complex disease with a strong genetic involvement. We aimed to identify novel, rare, highly penetrant risk variants combining family-based linkage analysis with whole-exome sequencing (WES). METHODS:Linkage analysis of 16 kindreds of South Italian ancestry was performed using an 'affected-only' strategy. Eight most informative trios composed of two familial cases and an intrafamilial control were selected for WES. High-priority variants in linked regions were identified and validated using Sanger sequencing. Custom TaqMan assays were designed and carried out in the 16 kindreds and an independent cohort of 240 IgAN patients and 113 control subjects. RESULTS:We found suggestive linkage signals in 12 loci. After sequential filtering and validation of WES data, we identified 24 private or extremely rare (MAF <0.0003) linked variants segregating with IgAN status. These were present within coding or regulatory regions of 23 genes that merged into a common functional network. The genes were interconnected by AKT, CTNNB1, NFKB, MYC and UBC, key modulators of WNT/β-catenin and PI3K/Akt pathways, which are implicated in IgAN pathogenesis. Overlaying publicly available expression data, genes/proteins with expression notably altered in IgAN were included in this immune-related network. In particular, the network included the glucocorticoid receptor gene, NR3C1, which is the target of corticosteroid therapy routinely used in the treatment of IgAN. CONCLUSION:Our findings suggest that disease susceptibility could be influenced by multiple rare variants acting in a common network that could provide the starting point for the identification of potential drug targets for personalized therapy.
journal_name
J Intern Medjournal_title
Journal of internal medicineauthors
Cox SN,Pesce F,El-Sayed Moustafa JS,Sallustio F,Serino G,Kkoufou C,Giampetruzzi A,Ancona N,Falchi M,Schena FP,European IgAN Consortium.doi
10.1111/joim.12565subject
Has Abstractpub_date
2017-02-01 00:00:00pages
189-205issue
2eissn
0954-6820issn
1365-2796journal_volume
281pub_type
杂志文章abstract::The socio-economic impact of Alzheimer's disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from...
journal_title:Journal of internal medicine
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journal_title:Journal of internal medicine
pub_type: 杂志文章
doi:10.1111/j.1365-2796.1992.tb00623.x
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abstract::Increasing evidence suggests that paraneoplastic syndromes may be mediated by tumour-related cytokine release, although the specific factor(s) involved remain poorly defined. Colony-stimulating factors (CSF) and interleukins (IL) promote colony growth in semi-solid media and, when administered in recombinant form, inc...
journal_title:Journal of internal medicine
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doi:10.1111/j.1365-2796.1993.tb00765.x
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abstract::We describe a 22-year-old female with systemic lupus erythematosus and lymphopenia, who developed septic arthritis of the right knee with Listeria monocytogenes type 1/2 A, whilst on low-dose methotrexate (MTX). So far, septic arthritis due to this microorganism has been reported in two other patients treated with low...
journal_title:Journal of internal medicine
pub_type: 杂志文章,评审
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journal_title:Journal of internal medicine
pub_type: 杂志文章
doi:10.1111/j.1365-2796.1995.tb01178.x
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journal_title:Journal of internal medicine
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journal_title:Journal of internal medicine
pub_type: 杂志文章
doi:10.1111/j.1365-2796.1992.tb00529.x
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journal_title:Journal of internal medicine
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doi:10.1111/j.1365-2796.1993.tb00663.x
更新日期:1993-02-01 00:00:00
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journal_title:Journal of internal medicine
pub_type: 杂志文章
doi:10.1111/joim.12801
更新日期:2018-10-01 00:00:00
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journal_title:Journal of internal medicine
pub_type: 杂志文章,评审
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更新日期:2015-02-01 00:00:00
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journal_title:Journal of internal medicine
pub_type: 杂志文章
doi:10.1111/j.1365-2796.2007.01871.x
更新日期:2007-12-01 00:00:00
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doi:10.1046/j.1365-2796.1999.00410.x
更新日期:1999-01-01 00:00:00
abstract::We present three patients with variant angina pectoris and episodes of cardiac arrest. All of them had typical clinical symptoms, ST-segment changes in electrocardiogram, and coronary artery spasm confirmed by arteriography. They were treated with high doses of calcium antagonists and nitrates. An automatic cardiovert...
journal_title:Journal of internal medicine
pub_type: 杂志文章
doi:10.1046/j.1365-2796.2002.01044.x
更新日期:2002-10-01 00:00:00
abstract::The fight against doping in sports commenced as a result of the death of a Danish cyclist during the Rome Olympic Games in 1960. The International Olympic Committee (IOC) established a Medical Commission (IOC-MC) which had the task of designing a strategy to combat the misuse of drugs in Olympic Sport. Some Internatio...
journal_title:Journal of internal medicine
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2796.2008.01993.x
更新日期:2008-08-01 00:00:00
abstract::APOA5 encodes a novel apolipoprotein (apo A-V) which appears to be a modulator of plasma triglyceride (TG). In apoA5 knock out mice plasma TG level increases almost fourfold, whereas in human APOA5 transgenic mice it decreases by 70%. Some SNPs in the APOA5 gene have been associated with variations in plasma TG in hum...
journal_title:Journal of internal medicine
pub_type: 杂志文章
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更新日期:2008-04-01 00:00:00
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journal_title:Journal of internal medicine
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doi:10.1046/j.1365-2796.1997.00177.x
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abstract::Pancreatic transplantation was performed in three patients with insulin-dependent diabetes mellitus in whom recurrent and severe episodes of hypoglycaemia had been found to be due to defective glucose counterregulation. Thus in these patients the spontaneous blood glucose recovery after insulin-induced hypoglycaemia (...
journal_title:Journal of internal medicine
pub_type: 杂志文章
doi:10.1111/j.1365-2796.1991.tb00484.x
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journal_title:Journal of internal medicine
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更新日期:2008-01-01 00:00:00
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journal_title:Journal of internal medicine
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journal_title:Journal of internal medicine
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更新日期:2006-04-01 00:00:00
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journal_title:Journal of internal medicine
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更新日期:2017-02-01 00:00:00
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journal_title:Journal of internal medicine
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更新日期:2011-08-01 00:00:00
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journal_title:Journal of internal medicine
pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2007-03-01 00:00:00
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journal_title:Journal of internal medicine
pub_type: 杂志文章,评审
doi:10.1111/joim.12912
更新日期:2019-09-01 00:00:00