A large study led by the University of Alabama at Birmingham found 10 new areas 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 are designed to interact with.
Osteoarthritis is a common, degenerative joint condition accruing healthcare costs in the U.S. alone of $880 million a year. Despite this, causative factors are still not well understood and there are limited treatment options available.
“As no effective medical interventions for disease modification are available, osteoarthritis often progresses to its end stage, at which time only surgical options are available, usually in the form of total joint replacement,” write Merry-Lynn McDonald, an associate professor at the University of Alabama, and colleagues.
“A more thorough understanding of genetic influences of osteoarthritis is essential to develop targeted personalized approaches to treatment, ideally long before the end stage is reached,” they add in the paper describing the work in Nature Genetics.
This study included 484,374 participants in the Million Veteran Program (163,015 participants) and UK Biobank (321,359 participants). Although the majority of participants from both studies were from White, European backgrounds (73-92%), the Million Veteran Program also included: 17.5% African Americans, 6.3% Hispanic, and 0.8% Asian participants. Similarly, the UK Biobank group included 2.2% people of African, 0.5% of East Asian, and 2.2% of South Asian origin.
The team performed a genome-wide association study (GWAS) to look for genetic associations with osteoarthritis in 140,025 cases and 344,349 controls across the two cohorts. As well as confirming several previous findings linking specific genetic variants with the condition, they also found 10 new areas of variation in the genome linked to osteoarthritis.
For example, there was an area 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 those with the condition and can be used as a biomarker of osteoarthritis progression.
The researchers report some signs of differences across ancestries, but say studies including larger populations of non-European ancestry populations are needed to investigate this in more depth.
The team analyzed their results to assess if already approved drugs exist that could be repurposed to treat osteoarthritis. “Our drug repurposing findings provide support for current physicians’ intuition in terms of prescription patterns of antiepileptics for osteoarthritis pain,” write the authors. “The antiepileptics gabapentin and pregabalin are increasingly prescribed to patients with osteoarthritis to help with pain, despite gaps in understanding of how they work for osteoarthritis patients.”
The team also found expression quantitative trait loci suggesting some anti-cancer and anti-acne drugs could also have potential for treating osteoarthritis.
“Many antineoplastic agents have antifibrotic properties. Synovial inflammation and fibrosis mark osteoarthritis progression, supporting the logic that some antineoplastic agents may have benefits for osteoarthritis,” write the researchers.
“Antiacne preparations include azaleic acid, which was decreased in urine in an osteoarthritis rat model. Additional research is merited to test whether azaleic acid in urine could serve as biomarker of osteoarthritis progression in humans.”
