Universität zu Köln

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

Full text not available from this repository.

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:	Creators Email ORCID ORCID Put Code Ng, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Thakkar, Dipti UNSPECIFIED UNSPECIFIED UNSPECIFIED Southam, Lorraine UNSPECIFIED UNSPECIFIED UNSPECIFIED Werker, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Ophoff, Roel UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Nothnagel, Michael UNSPECIFIED orcid.org/0000-0001-8305-7114 UNSPECIFIED Franke, Andre UNSPECIFIED orcid.org/0000-0003-1530-5811 UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Espirito-Santo, Ana Isabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Izadi, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Hennies, Hans Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Nanchahal, Jagdeep UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeggini, Eleftheria UNSPECIFIED UNSPECIFIED UNSPECIFIED Furniss, Dominic UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DISCOIDIN-DOMAIN RECEPTOR-2; EXTRACELLULAR-MATRIX; KINASE; EXPRESSION; COLLAGEN; OSTEOARTHRITIS; ACTIVATION; IMPUTATION; CELLS; PROLIFERATION Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21795