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Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes

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dc.contributor.author Wang B.
dc.contributor.author Carter R.E.
dc.contributor.author Jaffa M.A.
dc.contributor.author Nakerakanti S.
dc.contributor.author Lackland D.
dc.contributor.author Lopes-Virella M.
dc.contributor.author Trojanowska M.
dc.contributor.author Luttrell L.M.
dc.contributor.author Jaffa A.A.
dc.contributor.editor
dc.date Jun-10
dc.date.accessioned 2017-10-18T13:33:52Z
dc.date.available 2017-10-18T13:33:52Z
dc.date.issued 2010
dc.identifier 10.1136/jmg.2009.073098
dc.identifier.issn 222593
dc.identifier.uri http://hdl.handle.net/10938/20542
dc.description.abstract Background: The evidence for genetic susceptibility in the pathogenesis of diabetic nephropathy is well recognised, but the genes involved remain to be identified. It is hypothesised that mutations within the gene encoding connective tissue growth factor (CTGF-CCN2) will increase the propensity of diabetic subjects to develop nephropathy. Methods and results: Genomic screening was performed for single nucleotide polymorphisms (SNPs) within the CTGF gene in 862 subjects from the DCCT-EDIC cohort of type 1 diabetes. A novel SNP was identified in the promoter region that changes a C-G at the position -20. The frequency of GG genotype in microalbuminuric patients (albumin excretion rate (AER) 40 mg-24 h) is significantly greater than diabetics with AER 40 mg-24 h, p0.0001. The relative risk (RR) to develop microalbuminuria in diabetic subjects with the polymorphism is 3X higher than diabetic subjects without the polymorphism (RR 3.142, 95percent CI 1.9238 to 5.1249; p0.05). Kaplan-Meier survival curves demonstrated that the GG genotype group developed microalbuminuria and macroalbuminuria at a more rapid rate than the GC or CC genotypes. Functional studies demonstrated that the basal activity of the substituted allele-promoter (-20 GG allele) was significantly greater than that of the wild type promoter (-20 CC genotype). This higher level of basal activity of substituted allele CTGF-CCN2 promoter was abrogated upon suppression of Smad1 levels, indicating that SNP region in the CTGF-CCN2 promoter plays a vital role in the gene expression. Conclusions: These findings provide the first evidence that variants within the promoter region of the CTGF-CCN2 gene predisposes diabetic subjects to develop albuminuria and demonstrate that Samd1 controls the expression of CTGF-CCN2 promoter through this region.
dc.format.extent Pages: (391-397)
dc.language English
dc.publisher LONDON
dc.relation.ispartof Publication Name: Journal of Medical Genetics; Publication Year: 2010; Volume: 47; no. 6; Pages: (391-397);
dc.source Scopus
dc.subject.other GENBANK: AL354866, X92511
dc.title Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes
dc.type Article
dc.contributor.affiliation Wang, B., Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, United States
dc.contributor.affiliation Carter, R.E., Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, United States
dc.contributor.affiliation Jaffa, M.A., Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, United States, Epidemiology and Population Health Department, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon
dc.contributor.affiliation Nakerakanti, S., Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, United States
dc.contributor.affiliation Lackland, D., Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, United States
dc.contributor.affiliation Lopes-Virella, M., Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, United States
dc.contributor.affiliation Trojanowska, M., Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, United States
dc.contributor.affiliation Luttrell, L.M., Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, United States
dc.contributor.affiliation Jaffa, A.A., Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, United States, Department of Biochemistry, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
dc.contributor.authorAddress Jaffa, A. A.; Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, United States; email: jaffaa@musc.edu
dc.contributor.authorCorporate University: American University of Beirut; Faculty: Faculty of Health Sciences; Department: Epidemiology and Population Health;
dc.contributor.authorDepartment Epidemiology and Population Health
dc.contributor.authorDivision
dc.contributor.authorEmail jaffaa@musc.edu
dc.contributor.authorFaculty Faculty of Health Sciences
dc.contributor.authorInitials Wang, B
dc.contributor.authorInitials Carter, RE
dc.contributor.authorInitials Jaffa, MA
dc.contributor.authorInitials Nakerakanti, S
dc.contributor.authorInitials Lackland, D
dc.contributor.authorInitials Lopes-Virella, M
dc.contributor.authorInitials Trojanowska, M
dc.contributor.authorInitials Luttrell, LM
dc.contributor.authorInitials Jaffa, AA
dc.contributor.authorOrcidID
dc.contributor.authorReprintAddress Jaffa, AA (reprint author), Med Univ S Carolina, Dept Med, 114 Doughty St,POB 250776, Charleston, SC 29425 USA.
dc.contributor.authorResearcherID
dc.contributor.authorUniversity American University of Beirut
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dc.description.citedCount 9
dc.description.citedTotWOSCount 10
dc.description.citedWOSCount 8
dc.format.extentCount 7
dc.identifier.coden JMDGA
dc.identifier.pubmedID 20522428
dc.identifier.scopusID 77953705025
dc.publisher.address BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND
dc.relation.ispartOfISOAbbr J. Med. Genet.
dc.relation.ispartOfIssue 6
dc.relation.ispartofPubTitle Journal of Medical Genetics
dc.relation.ispartofPubTitleAbbr J. Med. Genet.
dc.relation.ispartOfVolume 47
dc.source.ID WOS:000278373000005
dc.type.publication Journal
dc.subject.otherChemCAS Smad1 protein, 444952-89-0
dc.subject.otherChemCAS Connective Tissue Growth Factor, 139568-91-5
dc.subject.otherChemCAS SMAD1 protein, human
dc.subject.otherChemCAS Smad1 Protein
dc.subject.otherIndex albumin
dc.subject.otherIndex connective tissue growth factor
dc.subject.otherIndex Smad1 protein
dc.subject.otherIndex adolescent
dc.subject.otherIndex adult
dc.subject.otherIndex albuminuria
dc.subject.otherIndex article
dc.subject.otherIndex binding site
dc.subject.otherIndex diabetic nephropathy
dc.subject.otherIndex female
dc.subject.otherIndex gene expression
dc.subject.otherIndex gene frequency
dc.subject.otherIndex genetic predisposition
dc.subject.otherIndex genetic risk
dc.subject.otherIndex genetic screening
dc.subject.otherIndex genetic susceptibility
dc.subject.otherIndex genetic variability
dc.subject.otherIndex genotype
dc.subject.otherIndex human
dc.subject.otherIndex insulin dependent diabetes mellitus
dc.subject.otherIndex macroalbuminuria
dc.subject.otherIndex major clinical study
dc.subject.otherIndex male
dc.subject.otherIndex microalbuminuria
dc.subject.otherIndex nucleotide sequence
dc.subject.otherIndex priority journal
dc.subject.otherIndex promoter region
dc.subject.otherIndex single nucleotide polymorphism
dc.subject.otherIndex survival
dc.subject.otherIndex TATA box
dc.subject.otherIndex urinary excretion
dc.subject.otherIndex wild type
dc.subject.otherIndex Adolescent
dc.subject.otherIndex Adult
dc.subject.otherIndex Base Sequence
dc.subject.otherIndex Cohort Studies
dc.subject.otherIndex Connective Tissue Growth Factor
dc.subject.otherIndex Diabetes Mellitus, Type 1
dc.subject.otherIndex Diabetic Nephropathies
dc.subject.otherIndex DNA Mutational Analysis
dc.subject.otherIndex Female
dc.subject.otherIndex Gene Frequency
dc.subject.otherIndex Genetic Predisposition to Disease
dc.subject.otherIndex Genotype
dc.subject.otherIndex Humans
dc.subject.otherIndex Kaplan-Meiers Estimate
dc.subject.otherIndex Male
dc.subject.otherIndex Polymorphism, Single Nucleotide
dc.subject.otherIndex Promoter Regions, Genetic
dc.subject.otherIndex RNA Interference
dc.subject.otherIndex Smad1 Protein
dc.subject.otherIndex Young Adult
dc.subject.otherKeywordPlus EARLY NATURAL-HISTORY
dc.subject.otherKeywordPlus STAGE RENAL-DISEASE
dc.subject.otherKeywordPlus KIDNEY-DISEASE
dc.subject.otherKeywordPlus FACTOR-BETA
dc.subject.otherKeywordPlus FOLLOW-UP
dc.subject.otherKeywordPlus COMPLICATIONS
dc.subject.otherKeywordPlus MELLITUS
dc.subject.otherKeywordPlus CELLS
dc.subject.otherKeywordPlus IDDM
dc.subject.otherKeywordPlus PROGRESSION
dc.subject.otherWOS Genetics and Heredity
dc.identifier.doi http://dx.doi.org/10.1136/jmg.2009.073098


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