Ng, Michael, Thakkar, Dipti, Southam, Lorraine, Werker, Paul, Ophoff, Roel, Becker, Kerstin, Nothnagel, Michael ORCID: 0000-0001-8305-7114, Franke, Andre ORCID: 0000-0003-1530-5811, Nuernberg, Peter, Espirito-Santo, Ana Isabel, Izadi, David, Hennies, Hans Christian, Nanchahal, Jagdeep, Zeggini, Eleftheria and Furniss, Dominic (2017). A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis. Am. J. Hum. Genet., 101 (3). S. 417 - 428. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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 x 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ng, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thakkar, DiptiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southam, LorraineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Werker, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ophoff, RoelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nothnagel, MichaelUNSPECIFIEDorcid.org/0000-0001-8305-7114UNSPECIFIED
Franke, AndreUNSPECIFIEDorcid.org/0000-0003-1530-5811UNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Espirito-Santo, Ana IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Izadi, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hennies, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nanchahal, JagdeepUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeggini, EleftheriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Furniss, DominicUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-217952
DOI: 10.1016/j.ajhg.2017.08.006
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 101
Number: 3
Page Range: S. 417 - 428
Date: 2017
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DISCOIDIN-DOMAIN RECEPTOR-2; EXTRACELLULAR-MATRIX; KINASE; EXPRESSION; COLLAGEN; OSTEOARTHRITIS; ACTIVATION; IMPUTATION; CELLS; PROLIFERATIONMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21795

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