| Title: | Shared genetic susceptibility between trigger finger and carpal tunnel syndrome: a genome-wide association study |
| Journal: | The Lancet Rheumatology |
| Published: | 21 Jul 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36043126/ |
| DOI: | https://doi.org/10.1016/s2665-9913(22)00180-1 |
| URL: | http://www.thelancet.com/article/S2665991322001801/pdf |
| Citations: | 8 (5 in last 2 years) as of 8 Aug 2024 |
Publication 12297
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Abstract
Background: Trigger finger and carpal tunnel syndrome are the two most common non-traumatic connective tissue disorders of the hand. Both of these conditions frequently co-occur, often in patients with rheumatoid arthritis. However, this phenotypic association is poorly understood. Hypothesising that the co-occurrence of trigger finger and carpal tunnel syndrome might be explained by shared germline predisposition, we aimed to identify a specific genetic locus associated with both diseases.</p>
Methods: In this genome-wide association study (GWAS), we identified 2908 patients with trigger finger and 436579 controls from the UK Biobank prospective cohort. We conducted a case-control GWAS for trigger finger, followed by co-localisation analyses with carpal tunnel syndrome summary statistics. To identify putative causal variants and establish their biological relevance, we did fine-mapping analyses and expression quantitative trait loci (eQTL) analyses, using fibroblasts from healthy donors (n=79) and tenosynovium samples from patients with carpal tunnel syndrome (n=77). We conducted a Cox regression for time to trigger finger and carpal tunnel syndrome diagnosis against plasma IGF-1 concentrations in the UK Biobank cohort.</p>
Findings: Phenome-wide analyses confirmed a marked association between carpal tunnel syndrome and trigger finger in the participants from UK Biobank (odds ratio [OR] 11·97, 95% CI 11·1-13·0; p<1 × 10-300). GWAS for trigger finger identified five independent loci, including one locus, DIRC3, that was co-localised with carpal tunnel syndrome and could be fine-mapped to rs62175241 (0·76, 0·68-0·84; p=5·03 × 10-13). eQTL analyses found a fibroblast-specific association between the protective T allele of rs62175241 and increased DIRC3 and IGFBP5 expression. Increased plasma IGF-1 concentrations were associated with both carpal tunnel syndrome and trigger finger in participants from UK Biobank (hazard ratio >1·04, p<0·02).</p>
Interpretation: In this GWAS, the DIRC3 locus on chromosome 2 was significantly associated with both carpal tunnel syndrome and trigger finger, possibly explaining their co-occurrence. The disease-protective allele of rs62175241 was associated with increased expression of long non-coding RNA DIRC3 and its transcriptional target, IGBP5, an antagonist of IGF-1 signalling. These findings suggest a model in which IGF-1 is a driver of both carpal tunnel syndrome and trigger finger, and in which the DIRC3-IGFBP5 axis directly antagonises fibroblastic IGF-1 signalling.</p>
Funding: Wellcome Trust, National Institute for Health Research, Medical Research Council.</p>
11 Authors
- Benjamin Patel
- Sam O Kleeman
- Drew Neavin
- Joseph Powell
- Georgios Baskozos
- Michael Ng
- Waheed-Ul-Rahman Ahmed
- David L Bennett
- Annina B Schmid
- Dominic Furniss
- Akira Wiberg
1 Application
| Application ID | Title |
|---|---|
| 22572 | Genetics and Epidemiology of Common Hand Conditions (GECHCo) |
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