Arthritis affects around 40% of the worldwide population over 70. Scientists have now discovered eight new genetic variants or loci in the largest genome-wide study (GWAS) of osteoarthritis to date, which seem to increase susceptibility to the most common form of arthritis. The findings, which have been published Online First in The Lancet raise the total number of osteoarthritis susceptibility genes isolated in European populations to 11.
Research leader, John Loughlin from Newcastle University in the UK states:
“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.”
As much as 60% of the various risks for osteoarthritis can be attributed to inherited factors, but even though scientists have conducted extensive research, it has been difficult to identify the genes involved. GWAS previously discovered three variants, i.e. GDF5, chromosome 7q22 and MCF2L. However these three variants only represent a tiny fraction of that risk, which suggests that the participant numbers in earlier studies may have been inadequate to identify genes with modest effect.
In their new study, Loughlin and his team compared genomes of over 7,400 people in the UK with severe hip and knee osteoarthritis, 80% of which had a total joint replacement, with over 11,000 unrelated controls. The team identified the most promising sites and replicated these in an independent group of nearly 7,500 individuals with osteoarthritis and approximately 43,000 individuals without osteoarthritis from countries, including Estonia, Iceland, the Netherlands, and the UK.
Whilst the findings confirmed the presence of the three earlier identified gene variants, it also discovered another eight sites linked to osteoarthritis. The team found that 5 of the new loci had an important link to the disease, whilst another three loci were approaching the threshold for genome-wide significance.
The team discovered that the strongest link was found in variant rs6976 on chromosome 3p21.1 in the region of the GNL3 gene. The GNL3’s encoded protein, called nucleostemin, plays a significant role in cell maintenance. “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,” explain the researchers.
The locations of the other three new loci, i.e. CHST11, PTHLH, and FTO are in regions of considerable biological interest. They regulate endochondral bone development within the cartilage, body weight, which is a strong risk factor for osteoarthritis and encode proteins involved in modulating cartilage proteoglycan, which have already been targeted by anti-osteoarthritis drugs.
The researchers conclude: “These results provide a basis for functional studies to identify the underlying causative variants, biological networks, and molecular cause of osteoarthritis.”
Marc C Hochberg and his team from Maryland University’s School of Medicine in Baltimore, USA write in an associated comment:
“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.”
Written by Petra Rattue