Abstract
Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10−8. As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research.
Highlights
Dupuytren disease (DD [might occur. MAP4K5 (MIM): 126900]) is a progressive fibroproliferative disease of the palmar fascia and the most common inherited disorder of the connective tissue
Because DD is associated with other forms of fibrosis, it may serve as an ideal human model system for fibrotic disease, and the routine excision of tissue as a part of treatment facilitates experimental medicine studies.[5]
Ethical Approval The study was approved by the Research Ethics Committee or equivalent at all institutions where the work was carried out: Oxfordshire Research Ethics Committee B/09/H0605/65 for the British Society for Surgery of the Hand Genetics of Dupuytren’s Disease (BSSH-GODD) study (UK), Medical Ethics Committee (METc) 2007/067 for the Genetic Origin of Dupuytren Disease (GODDAF) Study, and University of Cologne 14/292 for the German Dupuytren Study (Germany)
Summary
Dupuytren disease (DD [MIM: 126900]) is a progressive fibroproliferative disease of the palmar fascia and the most common inherited disorder of the connective tissue. It is the most frequent example of a tissue-specific fibrotic disease: others include pulmonary, renal, hepatic, and skin fibrosis. DD is characterized by the initial development of myofibroblast-rich nodules in the palm of the hand. These myofibroblasts express alpha-smooth muscle actin (a-SMA) and secrete types III and I collagen, leading to the formation of abnormal cords in the palm of the hand. Because DD is associated with other forms of fibrosis, it may serve as an ideal human model system for fibrotic disease, and the routine excision of tissue as a part of treatment facilitates experimental medicine studies.[5]
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