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Dolmans, G.H.* ; Werker, P.M.* ; Hennies, H.C.* ; Furniss, D.* ; Festen, E.A.* ; Franke, L.* ; Becker, K.* ; van der Vlies, P.* ; Wolffenbuttel, B.H.* ; Tinschert, S.* ; Toliat, M.R.* ; Nothnagel, M.* ; Franke, A.* ; Klopp, N. ; Wichmann, H.-E. ; Nürnberg, P.* ; Giele, H.* ; Ophoff, R.A.* ; Wijmenga, C* ; Dutch Dupuytren Study Group (*) ; German Dupuytren Study Group (*) ; LifeLines Cohort Study (*) ; BSSH-GODD Consortium (*)

Wnt signaling and Dupuytren's disease.

N. Engl. J. Med. 365, 307-317 (2011)
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BACKGROUND: Dupuytren's disease is a benign fibromatosis of the hands and fingers that leads to flexion contractures. We hypothesized that multiple genetic and environmental factors influence susceptibility to this disease and sought to identify susceptibility genes to better understand its pathogenesis. METHODS: We conducted a genomewide association study of 960 Dutch persons with Dupuytren's disease and 3117 controls (the discovery set) to test for association between the disease and genetic markers. We tested the 35 single-nucleotide polymorphisms (SNPs) most strongly associated with Dupuytren's disease (P<1×10(-4)) in the discovery set in three additional, independent case series comprising a total of 1365 affected persons and 8445 controls from Germany, the United Kingdom, and The Netherlands. RESULTS: Initially, we observed a significant genomewide association between Dupuytren's disease and 8 SNPs at three loci. Tests of replication and joint analysis of all data from 2325 patients with Dupuytren's disease and 11,562 controls yielded an association with 11 SNPs from nine different loci (P<5.0×10(-8)). Six of these loci contain genes known to be involved in the Wnt-signaling pathway: WNT4 (rs7524102) (P=2.8×10(-9); odds ratio, 1.28), SFRP4 (rs16879765) (P=5.6×10(-39); odds ratio, 1.98), WNT2 (rs4730775) (P=3.0×10(-8); odds ratio, 0.83), RSPO2 (rs611744) (P=7.9×10(-15); odds ratio, 0.75), SULF1 (rs2912522) (P=2.0×10(-13); odds ratio, 0.72), and WNT7B (rs6519955) (P=3.2×10(-33); odds ratio, 1.54). CONCLUSIONS: This study implicates nine different loci involved in genetic susceptibility to Dupuytren's disease. The fact that six of these nine loci harbor genes encoding proteins in the Wnt-signaling pathway suggests that aberrations in this pathway are key to the process of fibromatosis in Dupuytren's disease.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genetic susceptibility; Contracture; Catenin; Association; Management; Expression; Variants
Language english
Publication Year 2011
HGF-reported in Year 2011
ISSN (print) / ISBN 0028-4793
e-ISSN 1533-4406
Journal New England Journal of Medicine, The / NEJM
Quellenangaben Volume: 365, Issue: 4, Pages: 307-317 Article Number: , Supplement: ,
Publisher Massachusetts Medical Society (MMS)
Reviewing status Peer reviewed
Institute(s) Research Unit Molecular Epidemiology (AME)
Institute of Epidemiology (EPI)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30503 - Chronic Diseases of the Lung and Allergies
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504200-001
G-503900-001
PubMed ID 21732829
DOI 10.1056/NEJMoa1101029
Scopus ID 79960870883
Erfassungsdatum 2011-12-01
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