Wnt signaling and Dupuytren's disease

Guido H Dolmans, Paul M Werker, Hans C Hennies, Dominic Furniss, Eleonora A Festen, Lude Franke, Kerstin Becker, Pieter van der Vlies, Bruce H Wolffenbuttel, Sigrid Tinschert, Mohammad R Toliat, Michael Nothnagel, Andre Franke, Norman Klopp, H-Erich Wichmann, Peter Nürnberg, Henk Giele, Roel A Ophoff, Cisca Wijmenga, Dutch Dupuytren Study Group

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

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.

LanguageEnglish
Pages307-317
Number of pages11
JournalNew England Journal of Medicine
Volume365
Issue number4
DOIs
Publication statusPublished - 28 Jul 2011
Externally publishedYes

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Dupuytren Contracture
Odds Ratio
Single Nucleotide Polymorphism
Wnt Signaling Pathway
Fibroma
Disease Susceptibility
Contracture
Genetic Predisposition to Disease
Genetic Markers
Netherlands
Genes
Fingers
Germany
Hand

Cite this

Dolmans, G. H., Werker, P. M., Hennies, H. C., Furniss, D., Festen, E. A., Franke, L., ... Dutch Dupuytren Study Group (2011). Wnt signaling and Dupuytren's disease. New England Journal of Medicine, 365(4), 307-317. https://doi.org/10.1056/NEJMoa1101029
Dolmans, Guido H ; Werker, Paul M ; Hennies, Hans C ; Furniss, Dominic ; Festen, Eleonora A ; Franke, Lude ; Becker, Kerstin ; van der Vlies, Pieter ; Wolffenbuttel, Bruce H ; Tinschert, Sigrid ; Toliat, Mohammad R ; Nothnagel, Michael ; Franke, Andre ; Klopp, Norman ; Wichmann, H-Erich ; Nürnberg, Peter ; Giele, Henk ; Ophoff, Roel A ; Wijmenga, Cisca ; Dutch Dupuytren Study Group. / Wnt signaling and Dupuytren's disease. In: New England Journal of Medicine. 2011 ; Vol. 365, No. 4. pp. 307-317.
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Dolmans, GH, Werker, PM, Hennies, HC, Furniss, D, Festen, EA, Franke, L, Becker, K, van der Vlies, P, Wolffenbuttel, BH, Tinschert, S, Toliat, MR, Nothnagel, M, Franke, A, Klopp, N, Wichmann, H-E, Nürnberg, P, Giele, H, Ophoff, RA, Wijmenga, C & Dutch Dupuytren Study Group 2011, 'Wnt signaling and Dupuytren's disease', New England Journal of Medicine, vol. 365, no. 4, pp. 307-317. https://doi.org/10.1056/NEJMoa1101029

Wnt signaling and Dupuytren's disease. / Dolmans, Guido H; Werker, Paul M; Hennies, Hans C; Furniss, Dominic; Festen, Eleonora A; Franke, Lude; Becker, Kerstin; van der Vlies, Pieter; Wolffenbuttel, Bruce H; Tinschert, Sigrid; Toliat, Mohammad R; Nothnagel, Michael; Franke, Andre; Klopp, Norman; Wichmann, H-Erich; Nürnberg, Peter; Giele, Henk; Ophoff, Roel A; Wijmenga, Cisca; Dutch Dupuytren Study Group.

In: New England Journal of Medicine, Vol. 365, No. 4, 28.07.2011, p. 307-317.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Wnt signaling and Dupuytren's disease

AU - Dolmans, Guido H

AU - Werker, Paul M

AU - Hennies, Hans C

AU - Furniss, Dominic

AU - Festen, Eleonora A

AU - Franke, Lude

AU - Becker, Kerstin

AU - van der Vlies, Pieter

AU - Wolffenbuttel, Bruce H

AU - Tinschert, Sigrid

AU - Toliat, Mohammad R

AU - Nothnagel, Michael

AU - Franke, Andre

AU - Klopp, Norman

AU - Wichmann, H-Erich

AU - Nürnberg, Peter

AU - Giele, Henk

AU - Ophoff, Roel A

AU - Wijmenga, Cisca

AU - Dutch Dupuytren Study Group

PY - 2011/7/28

Y1 - 2011/7/28

N2 - 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.

AB - 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.

KW - Case-Control Studies

KW - Dupuytren Contracture

KW - Europe

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Signal Transduction

KW - Wnt Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1056/NEJMoa1101029

DO - 10.1056/NEJMoa1101029

M3 - Article

VL - 365

SP - 307

EP - 317

JO - New England Journal of Medicine

T2 - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 4

ER -

Dolmans GH, Werker PM, Hennies HC, Furniss D, Festen EA, Franke L et al. Wnt signaling and Dupuytren's disease. New England Journal of Medicine. 2011 Jul 28;365(4):307-317. https://doi.org/10.1056/NEJMoa1101029