Genetic link explains comorbid trigger finger and carpal tunnel syndrome

A common genetic link is associated with the frequent co-occurrence of trigger finger and carpal tunnel syndrome. Variants to 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 2,908 trigger-finger patients and 436,579 control participants using prospective cohort data from the UK Biobank (UK).

Researchers obtained fibroblasts from 79 healthy donors, tenosynovium samples after carpal tunnel decompression surgeries in 77 patients, and whole blood samples to extract DNA and plasma concentrations of insulin-like growth factor (IGF-1). Using these samples, they performed genome-wide association analysis, co-localization analysis, fine-mapping analysis, RNA sequencing, and quantitative trait loci analysis d expression (eQTL).


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Genome-wide association analysis revealed that the DIRC3 locus was independently associated with trigger finger and carpal tunnel syndrome. The genetic traits between trigger finger and carpal tunnel syndrome were also strongly correlated.

The co-localization analysis projected an 87% probability that trigger finger and carpal tunnel syndrome shared a causative genetic variant at the DIRC3 venue.

Fine mapping revealed covariates related to DIRC3 expression, including a single nucleotide polymorphism (SNP) at rs62175241 involving 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, was also positively correlated with IGFBP5 expression, the transcriptional target of DIRC3.

Researchers have confirmed increased levels of plasma IGF-1 in patients with both trigger finger and carpal tunnel syndrome. They hypothesized that increased fibroblast activity may have contributed to the pathogenesis of trigger finger and carpal tunnel syndrome.

Increased IGF-1 signaling was also correlated with the onset of diabetes. Patients with type 1 and type 2 diabetes and increased hemoglobin A1 C had a higher risk of developing comorbid trigger finger and carpal tunnel syndrome compared with trigger finger or carpal tunnel syndrome alone.

Limitations of the study include a lack of generalizability to patients outside of European ancestry, undersupply 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 could be explained at least in part by a shared germline predisposition, which acts to increase IGF-1 signaling in fibroblasts,” the authors conclude. ‘study. “Further research should determine whether this pathway could be a valid target for the pharmacological management of trigger finger and carpal tunnel syndrome.”

Disclosures: Several study authors have disclosed affiliations with biotechnology, pharmaceutical and/or device companies. Please see the original citation for a full list of author disclosures.

Reference

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

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