The first large multi-ancestry genetic study of osteoarthritis, or osteoarthritis, found 10 new genetic loci associated with osteoarthritis, and the results showed that some of the regions associated with osteoarthritis are found robustly in every ancestry of the population studied.
The first large multi-ancestry genetic study of osteoarthritis, or osteoarthritis, found 10 new genetic loci associated with osteoarthritis, and the results showed that some of the regions associated with osteoarthritis are found robustly in every ancestry of the population studied. The study also replicated other loci from previous OA studies and identified novel ancestry-specific genetic variants associated with OA in African American, Hispanic, and Asian American military veterans.
The team performed drug repurposing and found that genes thought to contribute to osteoarthritis included targets for existing drugs for cancer, epilepsy and acne, which may offer clues to etiology. and the possible treatment of osteoarthritis. Current physicians have intuitively prescribed antiepileptic drugs for osteoarthritis pain, despite gaps in understanding how they work in patients.
These findings, published in the journal Nature Genetics, add insight into how osteoarthritis common, a progressive joint disease, develops. Currently, little is known about the causes of the developing disease, and treatment is largely limited to pain and inflammation management. Since clinicians have no effective intervention to stop or slow OA, it often continues to the terminal stage, requiring total joint replacement.
A better understanding of the genetic influences of osteoarthritis should help identify targeted personalized approaches to treating patients, long before the final stage is reached, says Merry-Lynn McDonald, Ph.D., who led researchers from the University of Alabama at Birmingham, the Birmingham Veterans Health System, Birmingham, Alabama and several other Veterans Health System sites.
While many previous genome-wide association studies have found genetic loci associated with osteoarthritis, they have primarily involved people of white European ancestry. The study conducted by McDonald in collaboration with UAB researchers including Jasvinder Singh, MD, Joshua Richman, MD, Ph.D., and Hemant Tiwari, Ph.D., of UAB, used resources of 484,374 participants in the Million Veteran program from the US Department of Veterans Affairs and the United Kingdom Biobank, two huge biomedical databases containing extensive genetic and health information. These databases offered some opportunity for ancestry analysis, although they were still geared towards white Europeans.
The 163,015 OA participants in the Million Veteran program were 73.2% White European, 17.5% African American, 0.8% Asian American, and 6.3% Hispanic. The 321,359 OA participants in the UK Biobank were 91.4% White European, 2.2% African, 0.5% East Asian and 2.2% South Asian.
“Although we performed multi-ancestry and stratified analyses, most study subjects were of white European ancestry,” said McDonald, associate professor in UAB’s Department of Medicine, Division of Pulmonary Medicine. , Allergy and Critical Care, and Health Researcher. Birmingham Veterans Affairs Healthcare System scientist. “There remains a great need for further research to identify genetic variants and regions associated with OA that are robust to ancestry to develop precision medicine approaches that are generalizable to all patients. Our multi-genetic association study -ancestry of osteoarthritis represents only one step towards closing the gap in the lack of studies addressing the genetics of osteoarthritis in populations of non-European white ancestry.
Osteoarthritis has a profound impact on health. The annual cost of OA for US veterans alone is over $880 million per year. Osteoarthritis is the most common form of arthritis, often affecting the hands, hips, knees, feet and spine, and is the leading cause of leg disability in older people. Non-genetic risk factors for the disease include aging, being female, and being overweight. Yet osteoarthritis also has genetic risk factors and its heritability estimates are over 30%.
New genetic loci associated with osteoarthritis provide clues to the development of osteoarthritis. For example, a locus on chromosome 2 is in a gene for the fibulin-3 protein. “Fibulins are known to contribute to the elasticity and functional integrity of connective tissues,” McDonald said. “Fibulin-3 levels in serum and urine correlate with the incidence and progression of osteoarthritis and can be used as biomarkers.”
Another example is a locus on chromosome 3 in the G-type protein tyrosine phosphatase receptor gene, which has been shown to be hydroxymethylated in tissues that form cartilage in patients with osteoarthritis. Another example is that of two independent osteoarthritis-associated loci on chromosomes 11 and 12 at genes known to regulate the body’s circadian clock, which has been implicated in osteoarthritis.
The discovery of genes associated with osteoarthritis that are also the targets of existing cancer, epilepsy and acne drugs could lead to repurposing these drugs against osteoarthritis. Current physicians have intuitively prescribed antiepileptic drugs for osteoarthritis pain, despite gaps in understanding how they work in patients.
When it comes to cancer and acne drugs, “many anti-neoplastic agents have anti-fibrotic properties,” McDonald said. “Synovial inflammation and fibrosis mark the progression of OA, supporting the logic that some antineoplastic agents may have beneficial effects in OA. Anti-acne preparations include azaleic acid, which is decreased in urine in a rat model with osteoarthritis.
McDonald’s urges follow-ups to this current study. “The multi-ancestry OA-associated variants identified in the current report only begin to fill the gap in terms of identifying ancestry-independent OA-associated variants needed to advance the development of polygenic risk,” she said. “Larger sample sizes of individuals from ancestral and ethnic diversity are needed to continue to fuel progress and address the discovery bias imposed by previous white-focused European research.”
This work was only possible through a massive and successful ongoing effort to recruit veterans across the United States, including the Birmingham VA, complemented by cutting-edge data science approaches by bioinformaticians at the Team UAB: Preeti Lakshman Kumar, Ashwathy Nair and Vinodh Srinivasasainagendra. “It was both a daunting and exciting experience to have this phenomenal team perform genetic analyzes for over 400,000 people,” McDonald said.
Co-authors with McDonald on the article, “New genetic loci associated with osteoarthritis in multi-ancestry analyzes in the Million Veteran and UK Biobank program”, are Preeti Lakshman Kumar, Ashwathy Nair, Alison P. Rocco, Ava C. Wilson, Joe W. Chiles, and Sarah A. Pinson, UAB Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine; Vinodh Srinivasasainagendra and Hemant K. Tiwari, Department of Biostatistics, UAB School of Public Health; Joshua S. Richman, UAB Department of Surgery; Richard A. Dennis and Vivek Jagadale, Central Arkansas Veterans Health System, Little Rock; Cynthia J. Brown, Louisiana State University Health Sciences Center, New Orleans; Saiju Pyarajan, Boston Veterans Health System, Boston, Massachusetts; Marcas M. Bamman, UAB Department of Cellular, Developmental and Integrative Biology; and Jasvinder A. Singh, Department of Epidemiology, UAB School of Public Health.
Kumar, Nair, Srinivasasainagendra, Richman, Brown, Bamman and Singh also have appointments in the Birmingham Veterans Health System.
Support came from the Office of Research and Development, Veterans Health Administration, award I01RX002745.
Medicine, Surgery, and Cellular, Developmental, and Integrative Biology are departments of the UAB Marnix E. Heersink Faculty of Medicine.
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