Plastic surgeons and geneticists find genetic loci for Dupuytren's disease

UMCG plastic surgeons and geneticists reveal genetic susceptibility for Dupuytren's disease

PhD student and surgeon-in-training Guido Dolmans has completed a nationwide study into the genetic susceptibility for Dupuytren’s disease, working under the supervision of plastic surgeon Paul Werker and geneticist Cisca Wijmenga of the UMCG, and others from six hospitals in the Netherlands. This disease leads to malformation (contraction) in the fingers, which can seriously hamper use of the hand. It is estimated that 5-10% of people over the age of 50 suffer from Dupuytren. The research has shown that genetic factors play an important role in the development of this disease. Nine genes associated with the disease have been mapped, shedding new light into the development of the disease. This study is the first to demonstrate the value of LifeLines, the UMCG’s genetic databank. The results have just been published in the prestigious New England Journal of Medicine.

Wnt Signaling and Dupuytren's Disease

Guido H. Dolmans, M.D., Paul M. Werker, M.D., Ph.D., Hans C. Hennies, Ph.D., Dominic Furniss, M.D., Ph.D., Eleonora A. Festen, M.D., Ph.D., Lude Franke, Ph.D., Kerstin Becker, M.S., Pieter van der Vlies, B.S., Bruce H. Wolffenbuttel, M.D., Ph.D., Sigrid Tinschert, M.D., Mohammad R. Toliat, Ph.D., Michael Nothnagel, Ph.D., Andre Franke, Ph.D., Norman Klopp, Ph.D., H.-Erich Wichmann, M.D., Ph.D., Peter Nürnberg, Ph.D., Henk Giele, M.D., Ph.D., Roel A. Ophoff, Ph.D., and Cisca Wijmenga, Ph.D. for the Dutch Dupuytren Study Group, the German Dupuytren Study Group, the LifeLines Cohort Study, and the BSSH–GODD Consortium.

N Engl J Med . 2011 Jul 28;365(4):307-17. Epub 2011 Jul 6. Link to Free Article (full text)

 

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.

Link to free article in New England J Med