Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 365, Issue 4, Pages 307-317Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1101029
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Funding
- University Medical Center Groningen
- University of Groningen, the Netherlands
- German Ministry of Education and Research through the German National Genome Research Network
- German Research Foundation Cluster of Excellence Inflammation at Interfaces
- Academy of Medical Sciences
- Wellcome Trust
- Oxford University [MRF/2009/HT/1932]
- Netherlands Organization of Scientific Research [NWO 175.010.2007.006]
- Dutch government
- Ministries of Economic Affairs, Education, Culture and Science, and Health, Welfare and Sports
- Northern Netherlands Collaboration of Provinces
- Province of Groningen
- Dutch Kidney Foundation
- Dutch Diabetes Research Foundation
- Helmholtz Center Munich
- German Research Center for Environmental Health
- Munich Center of Health Sciences
- WTCCC [076113, 085475]
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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< 1x10-4) 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< 5.0x10(-8)). Six of these loci contain genes known to be involved in the Wnt-signaling pathway: WNT4 (rs7524102) (P = 2.8x10(-9); odds ratio, 1.28), SFRP4 (rs16879765) (P = 5.6x10-39; odds ratio, 1.98), WNT2 (rs4730775) (P = 3.0x10(-8); odds ratio, 0.83), RSPO2 (rs611744) (P = 7.9x10(-15); odds ratio, 0.75), SULF1 (rs2912522) (P = 2.0x10(-13); odds ratio, 0.72), and WNT7B (rs6519955) (P = 3.2x10(-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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