A large study led by the University of Alabama at Birmingham found 10 new regions in the genome linked to osteoarthritis, as well as potential drug candidates that could be repurposed to treat osteoarthritis based on the molecular targets they were designed to target. interact.
Osteoarthritis is a common, degenerative joint disease that accounts for $880 million in healthcare costs per year in the US alone. Despite this, causative factors are still not well understood and limited treatment options are available.
“Because no effective medical interventions for disease modification are available, osteoarthritis often progresses to its terminal stage, after which only surgical options are available, usually in the form of total joint replacement,” writes Merry-Lynn McDonald, an associate professor at the University of Alabama. , and colleagues.
“A deeper understanding of the genetic influences of osteoarthritis is essential to develop targeted personalized approaches to treatment, ideally long before end-stage,” they add in the paper describing the work in Natural genetics.
This study included 484,374 participants in the Million Veteran Program (163,015 participants) and UK Biobank (321,359 participants). While the majority of participants in both studies were of white European background (73-92%), the Million Veteran Program also included: 17.5% African American, 6.3% Hispanic, and 0.8% Asian Attendees. Similarly, the UK Biobank group included 2.2% of people of African, 0.5% of East Asian and 2.2% of South Asian descent.
The team conducted a genome-wide association study (GWAS) to look for genetic associations with osteoarthritis in 140,025 cases and 344,349 controls in the two cohorts. In addition to confirming several previous findings linking specific genetic variants to the condition, they also found 10 new regions of variation in the genome associated with osteoarthritis.
For example, there was a region on chromosome 2 within the EFEMP1 gene encoding the protein fibulin-3, which is known to contribute to the elasticity of connective tissue. Fibulin 3 levels vary in people with the condition and can be used as a biomarker of osteoarthritis progression.
The researchers report some signs of ancestry differences, but say studies with larger populations of non-European ancestry are needed to investigate this in more depth.
The team analyzed their results to assess whether there are already approved drugs that could be reused to treat osteoarthritis. “Our drug repurposing findings support current physicians’ intuition in terms of antiepileptic drug prescribing patterns for osteoarthritis pain,” the authors write. “The antiepileptic drugs gabapentin and pregabalin are increasingly being prescribed to patients with osteoarthritis to help with pain, despite gaps in understanding how they work for osteoarthritis patients.”
The team also found loci of expression quantitative trait, suggesting that some anti-cancer and anti-acne drugs may also have potential for the treatment of osteoarthritis.
“Many antineoplastic agents have antifibrotic properties. Synovial inflammation and fibrosis mark the progression of osteoarthritis, supporting the logic that some antineoplastic agents may have benefits for osteoarthritis,” the researchers write.
“Antiacne preparations included azaleic acid, which was reduced in urine in a rat model of osteoarthritis. Additional research is worthwhile to test whether urinary azaleic acid could serve as a biomarker for the progression of osteoarthritis in humans.”