Newly identified genetic risk factors for osteoarthritis

30 Dec 2021

Osteoarthritis is a leading cause of disability and a source of societal cost in the elderly that is becoming more prevalent especially with increasing obesity and number of joint injuries.1 The findings of a recent milestone meta-analysis deciphering the genetics of knee, hip, finger, thumb, and spine osteoarthritis across 826,690 individuals of European and East Asian descent, of whom 177,517 have osteoarthritis, were recently published in CELL.2 This study identified 52 previously unknown osteoarthritis genetic risk variants including SOX5 and CHST3 genes, overlapping genetic components in different osteoarthritis subtypes and pathology, and an association between the genetic components and pain-related phenotypes and other traits, providing insight into the key molecular players as potential drug targets.2

Osteoarthritis is a common disabling disease increasing the health and economic burden on affected individuals.1 Its prevalence is peaking due to the combined effects of aging, increasing obesity and increasing number of joint injuries.1 It is considered a complex chronic degenerative disease involving the whole joint and characterized by cartilage degeneration, subchondral bone thickening, osteophyte formation, synovial inflammation, and structural alterations of the joint capsule, ligaments and associated muscles.2 Genetics is estimated to contribute to 40% to 80% of osteoarthritis with a stronger contribution in hand and hip osteoarthritis than knee osteoarthritis.1 Recently, genome-wide association studies (GWAS) have provided a better understanding of the genetic background of osteoarthritis.2 However, the identified independent risk variants explain a few of the phenotypic variances and are mainly related to knee and hip osteoarthritis.2

To date, the typical management of osteoarthritis is considered palliative and reactive, and the guidelines recommend non-pharmacological methods as first-line treatment with symptom alleviation through pain relief and arthroplasty.1

Scientists from the LKS Faculty of Medicine, The University of Hong Kong (HKUMed), contributing as part of the ‘Genetics of Osteoarthritis (GO)’ consortium to the GWAS meta-analysis across the knee, hip, finger, thumb, and spine osteoarthritis phenotypes in 826,690 individuals from 9 populations, of whom 177,517 had osteoarthritis.2 The results of the study published in CELL found 100 unique variants independently associated with osteoarthritis across 11 osteoarthritis phenotypes.2 Of those, 52 have not been previously associated with any osteoarthritis phenotype, and the new signal nucleotide variants (SNVs) identified included CHST3 and SOX5 genes.2 CHST3 was one of the genes with the highest levels of confidence of involvement having 6 different lines of supporting evidence.2 

A previous GWAS meta-analysis of chronic back pain identified three novel genes significantly associated with chronic back pain, including SOX5, and suggested possible shared genetic mechanisms with other traits such as osteoarthritis and lumbar disc.3 The Hong Kong team had also previously found CHST3, an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for lumbar disc degeneration and showed that patients harboring CHST3 mutations appeared to have disc abnormalities consistent with earlier onset of degeneration.4

Additionally, some variants were seen in specific joints while the majority (60%) were genome-wide significantly associated with more than one osteoarthritis phenotype.2 Even though multiple core pathways are behind osteoarthritis pathology, no common genetic osteoarthritis SNVs have been detected before the most recent findings of the study that has identified 42 SNVs associated with multiple osteoarthritis joint sites.2 These signals could be prime candidates for drug development since they are likely to represent a common underlying mechanism in osteoarthritis pathology.2

Moreover, osteoarthritis subtypes were found to have overlapping genetic components, and further examination of the relationship between the genetic components and other traits revealed a significant association with anthropometric traits such as BMI, obesity, weight, fat mass, type 2 diabetes, smoking behavior, bone mineral density, and several pain phenotypes.2 This study also found a previously undetected high correlation between osteoarthritis and sciatica, fibromyalgia, headaches, and other back pain phenotypes, which was the highest with spine osteoarthritis.2

Professor Leong Chi-Yan John, emeritus and honorary professor of the department of orthopedics and traumatology at HKUMed, mentioned that many patients with disc degeneration and osteoarthritis suffer from back pain, and only symptomatic treatment is available. Hence, knowing the genes responsible for osteoarthritis is a major advancement towards the possibility of developing new specific drugs for treatment.

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