University of Huddersfield Repository A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis
University of Huddersfield Repository A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis
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哈德斯菲尔德大学资料库一项掌腱膜挛缩症的全基因组关联研究揭示了与纤维化有关的 17 种其他变异
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通讯作者：
Vanessa Mertins
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作者：
Vanessa Mertins
Dupuytren病的全基因组关联研究揭示了17个与纤维化有关的其他变异体患有Dupuytren病（DD）的个体通常被多个专业的医生和外科医生看到。这是一种越来越常见的致残性掌筋膜纤维增生性疾病，可导致手指挛缩，并与其他组织特异性纤维病相关。DD影响5%至25%的欧洲血统的人，是最常见的结缔组织遗传性疾病。我们进行了迄今为止最大的GWAS，在英国的DD手术确诊的个人，在英国，荷兰和德国的个人复制。我们验证了所有9个先前描述的信号的关联，并发现了17个额外的变体，p % 5 3 10（cid：1）8。作为原理证明，我们证明了在手术标本来源的DD成肌纤维细胞中，统计学上相关性最强的变体的高风险基因型与可溶性WNT拮抗剂SFRP 4分泌减少的相关性。这些结果强调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识到在纤维化中发挥作用的基因，开辟了新的研究途径，可能导致更普遍的DD和纤维化的新治疗方法。DD代表了纤维化研究的理想人类模型疾病。
A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis. 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 3 10 (cid:1) 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 spec-imen-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.