Osteoarthritis susceptibility: eight potential genes discovered

The largest genome-wide association study (GWAS) of osteoarthritis to date, published Online First in The Lancet, has uncovered eight new genetic variants or loci that appear to increase susceptibility to the most common form of arthritis, which affects about 40% of the world population older than 70 years. These findings bring the total number of osteoarthritis susceptibility genes isolated in European populations to 11.

“The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Our findings provide some insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention”, explains John Loughlin from Newcastle University in the UK, who led the research (funded by Arthritis Research UK).

Inherited factors could account for as much as 60% of the variation in risk for osteoarthritis. But despite extensive efforts, it has proved difficult to identify the genes involved. The three variants discovered in GWAS to date (GDF5, chromosome 7q22, and MCF2L) account for only a small fraction of that risk, suggesting that the number of participants in previous studies might not have been large enough to identify genes with modest effect.

Here, Loughlin and colleagues compared the genomes of more than 7400 people with severe hip and knee osteoarthritis (80% of whom had undergone total joint replacement) with over 11 000 unrelated controls from the UK. The most promising sites identified were then replicated in an independent group of almost 7500 people with osteoarthritis and about 43 000 individuals without the condition from Iceland, Estonia, the Netherlands, and the UK.

Results confirmed the three previously reported gene variants and found a further eight sites associated with osteoarthritis. Five of the new loci were significantly associated with the disease and an additional three loci were approaching the threshold for genome-wide significance.

The strongest association was variant rs6976 on chromosome 3p21.1 in the region of the GNL3 gene whose encoded protein (nucleostemin) plays an important role in cell maintenance. The authors explain: “Nucleostemin protein levels were substantially increased in cultured chondrocytes [cells usually embedded in cartilage matrix] from patients with osteoarthritis compared with controls, raising the possibility that this gene might be functionally important in the pathogenesis of osteoarthritis.”

Three other new loci (CHST11, PTHLH, and FTO) are located in regions of considerable biological interest that encode proteins involved in the modulation of cartilage proteoglycan (already targeted by anti-osteoarthritis drugs such as chondroitin sulphate), the regulation of endochondral (within cartilage) bone development, and body weight (a strong risk factor for osteoarthritis).

The authors conclude: “These results provide a basis for functional studies to identify the underlying causative variants, biological networks, and molecular cause of osteoarthritis.”

In a linked Comment, Marc C Hochberg and colleagues from University of Maryland School of Medicine, Baltimore, USA say: “The challenge will be to connect the biology of these genes to the development and progression of osteoarthritis and to investigate the therapeutic potential of these pathways for disease prevention and treatment.”