A common genetic link is associated with the frequent co-occurrence of trigger finger and carpal tunnel syndrome. Variations at DIRC3 also increase fibroblast activity and correlate with diabetes. These findings were published in The Lancet Rheumatology.
Researchers sought to identify a shared genetic predisposition in patients with trigger finger and carpal tunnel syndrome. They conducted a genome-wide association study of 2908 patients with trigger finger and 436,579 control participants using data from the United Kingdom (UK) Biobank prospective cohort.
The researchers obtained fibroblasts from 79 healthy donors, tenosynovium samples following carpal tunnel decompression surgeries in 77 patients, and whole blood samples to extract DNA and insulin-like growth factor-1 (IGF-1) plasma concentrations. Using these samples, they performed a genome-wide association analysis, a co-localization analysis, a fine-mapping analysis, RNA sequencing, and an expression quantitative trait loci (eQTL) analysis.
The genome-wide association analysis found that the DIRC3 locus was independently associated with trigger finger and carpal tunnel syndrome. Genetic traits between trigger finger and carpal tunnel syndrome were also highly correlated.
The co-localization analysis projected an 87% probability that trigger finger and carpal tunnel syndrome shared a causal genetic variant at the DIRC3 locus.
Fine-mapping revealed co-variants related to DIRC3 expression, including a single-nucleotide polymorphism (SNP) at rs62175241 involving in regulation of fibroblast activity, and two binding motifs (KLF16 and KLF18) involved in transcription.
Analysis via eQTL showed that the T allele of rs62175241, which protects against trigger finger and carpal tunnel, also positively correlated with IGFBP5 expression, the transcriptional target of DIRC3.
The researchers confirmed increased levels of plasma IGF-1 in patients with both trigger finger and carpal tunnel syndrome. They hypothesized that increased fibroblastic activity may have contributed to the pathogenesis of both trigger finger and carpal tunnel syndrome.
Increased IGF-1 signaling also correlated with onset of diabetes. Patients with type 1 and type 2 diabetes and increased hemoglobin A1c levels had higher risk for developing comorbid trigger finger and carpal tunnel syndrome compared with either trigger finger or carpal tunnel syndrome alone.
Limitations of the study include a lack of generalizability to patients outside of European ancestry, underpowering for low-frequency variants, and a lack of ability to replicate all 5 trigger finger loci.
“The long-established co-occurrence of trigger finger and carpal tunnel syndrome might be at least partly explained by a shared germline predisposition, which acts to increase IGF-1 signaling in fibroblasts,” the study authors conclude. “Further research should determine whether this pathway might be a valid target for pharmacological management of trigger finger and carpal tunnel syndrome.”
Disclosures: Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Patel B, Kleeman SO, Neavin D, et al. Shared genetic susceptibility between trigger finger and carpal tunnel syndrome: a genome-wide association study. The Lancet Rheumatology. 2022;4(8):e556-e565. doi:10.1016/S2665-9913(22)00180-1