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

doi:10.1056/NEJMoa1101029

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 journal › Article › peer-review

189 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.

Original language	English
Pages (from-to)	307-317
Number of pages	11
Journal	New England Journal of Medicine
Volume	365
Issue number	4
DOIs	https://doi.org/10.1056/NEJMoa1101029
Publication status	Published - 28 Jul 2011
Externally published	Yes

Access to Document

10.1056/NEJMoa1101029

Cite this

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 (2011). Wnt signaling and Dupuytren's disease. New England Journal of Medicine, 365(4), 307-317. https://doi.org/10.1056/NEJMoa1101029

@article{ef7dde16d01d464b958ed638bb374b70,

title = "Wnt signaling and Dupuytren's disease",

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.",

keywords = "Case-Control Studies, Dupuytren Contracture, Europe, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Signal Transduction, Wnt Proteins, Journal Article, Research Support, Non-U.S. Gov't",

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

year = "2011",

month = jul,

day = "28",

doi = "10.1056/NEJMoa1101029",

language = "English",

volume = "365",

pages = "307--317",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "4",

}

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

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

C2 - 21732829

VL - 365

SP - 307

EP - 317

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 4

ER -

Wnt signaling and Dupuytren's disease

Abstract

Access to Document

Fingerprint

Cite this