Ng Michael, Thakkar Dipti, Southam Lorraine, Werker Paul, Ophoff Roel, Becker Kerstin, Nothnagel Michael, Franke Andre, Nürnberg Peter, Espirito-Santo Ana Isabel, Izadi David, Hennies Hans Christian, Nanchahal Jagdeep, Zeggini Eleftheria, Furniss Dominic
Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Science, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7HE, UK.
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Am J Hum Genet. 2017 Sep 7;101(3):417-427. doi: 10.1016/j.ajhg.2017.08.006.
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. 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.
患有掌腱膜挛缩症（DD）的患者在多个专科的内科医生和外科医生处都很常见。它是一种越来越常见且致残的掌腱膜纤维增生性疾病，会导致手指屈曲挛缩，并与其他组织特异性纤维化有关。DD在5%至25%的欧洲血统人群中出现，是最常见的遗传性结缔组织疾病。我们对来自英国的经手术验证诊断为DD的个体进行了迄今为止最大规模的全基因组关联研究（GWAS），并在英国、荷兰和德国个体中进行了重复验证。我们验证了所有九个先前描述的信号的关联性，并发现了另外17个p≤5×10的变异。作为原理验证，我们在手术标本来源的DD肌成纤维细胞中证明了统计学上最强烈关联变异处的高危基因型与可溶性WNT拮抗剂SFRP4分泌减少之间的相关性。这些结果突出了参与纤维化发病机制的重要途径，包括WNT信号传导、细胞外基质调节和炎症。此外，许多相关基因座包含迄今未被认为在纤维化中起作用的基因，开辟了新的研究途径，可能会为DD和更普遍的纤维化带来新的治疗方法。DD是纤维化研究的理想人类模型疾病。
