DIRC3-IGFBP5 is a shared genetic risk locus and therapeutic target for carpal tunnel syndrome and trigger finger
DIRC3-IGFBP5 is a shared genetic risk locus and therapeutic target for carpal tunnel syndrome and trigger finger
Abstract Trigger finger (TF) and carpal tunnel syndrome (CTS) are two common non-traumatic hand disorders that frequently co-occur. By identifying TF and CTS cases in UK Biobank (UKB), we confirmed a highly significant phenotypic association between the diseases. To investigate the genetic basis for this association we performed a genome-wide association study (GWAS) including 2,908 TF cases and 436,579 European controls in UKB, identifying five independent loci. Colocalization with CTS summary statistics identified a co-localized locus at DIRC3 (lncRNA), which was replicated in FinnGen and fine-mapped to rs62175241. Single-cell and bulk eQTL analysis in fibroblasts from healthy donors (n=79) and tenosynovium samples from CTS patients (n=77) showed that the disease-protective rs62175241 allele was associated with increased DIRC3 and IGFBP5 expression. IGFBP5 is a secreted antagonist of IGF-1 signaling, and elevated IGF-1 levels were associated with CTS and TF in UKB, thereby implicating IGF-1 as a driver of both diseases.
Bennett David L.、Schmid Annina、Wiberg Akira、Neavin Drew、Baskozos Georgios、Furniss Dominic、Kleeman Sam O.、Patel Benjamin、Powell Joseph、Ng Michael、Ahmed Waheed-Ul-Rahman
University of Oxford, Nuffield Department of Clinical Neurosciences, John Radcliffe HospitalUniversity of Oxford, Nuffield Department of Clinical Neurosciences, John Radcliffe HospitalUniversity of Oxford, NDORMS, Botnar Research CentreGarvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical ResearchUniversity of Oxford, Nuffield Department of Clinical Neurosciences, John Radcliffe HospitalUniversity of Oxford, NDORMS, Botnar Research CentreCold Spring Harbor LaboratoryDepartment of Plastic and Reconstructive Surgery, Southmead Hospital, North Bristol NHS TrustGarvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research||UNSW Cellular Genomics Futures Institute, University of New South WalesUniversity of Oxford, NDORMS, Botnar Research CentreUniversity of Oxford, NDORMS, Botnar Research Centre
医学研究方法基础医学遗传学
Bennett David L.,Schmid Annina,Wiberg Akira,Neavin Drew,Baskozos Georgios,Furniss Dominic,Kleeman Sam O.,Patel Benjamin,Powell Joseph,Ng Michael,Ahmed Waheed-Ul-Rahman.DIRC3-IGFBP5 is a shared genetic risk locus and therapeutic target for carpal tunnel syndrome and trigger finger[EB/OL].(2025-03-28)[2025-06-14].https://www.medrxiv.org/content/10.1101/2021.10.07.21264697.点此复制
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