Gene discovery may lead to new treatments for osteoarthritis

Scientists have uncovered 52 new genetic changes linked to osteoarthritis which they say may help develop new treatments for the disabling condition. An international team of scientists analysed the genomes of over 77,000 people with osteoarthritis.

The findings, revealed new genes and biological pathways linked to osteoarthritis, which doubles the number of genetic regions associated with the disease.

They could also help identify starting points for new medicines and highlight opportunities for existing medicines to be evaluated in osteoarthritis, researchers said.

Osteoarthritis is a degenerative disease in which a person's joints become damaged, stop moving freely and become painful. There is no disease-modifying treatment for osteoarthritis.

The disease is managed with pain relief medications and often culminates in joint replacement surgery, which has variable outcomes.

"Osteoarthritis is the leading cause of chronic disability worldwide and this study represents the largest genetic epidemiological study to date in our attempts to understand what makes one person more likely to develop the disease than another," said  a professor.

"As well as looking at inherited factors that underpin disease susceptibility, we also looked at how genes link together to form pathways that underpin disease biology," the Prof. said.

"This helps us to identify key points towards which we could target the development of new treatments for the disease. Here we show data to support the repurposing of existing treatments, some drugs that are already in development, and also novel avenues for drug exploration," he said.

To uncover the genetics underpinning osteoarthritis, scientists analysed the whole genomes of over 77,000 people with osteoarthritis and over 370,000 healthy people.

The team studied many different types of osteoarthritis, including in knee and hip joints.

"We found over 50 new genetic changes that increase the risk of developing osteoarthritis. This is a major step forward in developing treatments to help the millions of people suffering from the disease," the Prof. said.

In order to discover which genes cause osteoarthritis, the team incorporated additional functional genomic data and analysed gene activity by measuring gene expression down to the protein level.

The team integrated genetic and proteomic data on tissue taken from patients undergoing joint replacement surgery. By incorporating many different data sets, scientists were able to identify which genes were likely to be causal for osteoarthritis.

Ten of the genes were highlighted as targets of existing drugs, which are either in clinical development or approved for use against osteoarthritis and other diseases.

These include the drugs INVOSSA, which is registered for knee osteoarthritis, and LCL-161, a drug in clinical development for the treatment of breast cancer, leukemia and myeloma.

The team suggest that the ten drugs highlighted would be good candidates for testing in osteoarthritis.

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New osteoarthritis genes discovered

In the largest study of its kind, nine novel genes for osteoarthritis have been discovered by scientists. Results of the study, published recently could open the door to new targeted therapies for this debilitating disease in the future. 
 
Almost nine million people in the UK suffer from osteoarthritis, a degenerative joint disease in which a person's joints become damaged, stop moving freely and become painful. Osteoarthritis is the most prevalent musculoskeletal disease and a leading cause of disability worldwide.

There is no treatment for osteoarthritis. The disease is managed with pain relief and culminates in joint replacement surgery, which has variable outcomes.

In the largest study of its kind, scientists investigated the genetics behind osteoarthritis, as well as the diseases and traits that are linked to it. To understand more about the genetic basis of osteoarthritis, the team studied 16.5 million DNA variations from the resource. Following combined analysis in up to 30,727 people with osteoarthritis and nearly 300,000 people without osteoarthritis in total—the controls—scientists discovered nine new genes that were associated with osteoarthritis, a significant result for this disease.

The senior author said: "Osteoarthritis is challenging to study because the disease can vary among people, and also between the different joints affected, for example knee, hip, hand and spine. Using data from the  resource, we have undertaken the largest genetic study of osteoarthritis to date and uncovered nine new genes associated with the disease."
Researchers then investigated the role of the nine new genes in osteoarthritis, by studying both normal cartilage and diseased cartilage from individuals who had a joint replacement.

The team looked for genes that were active in the progression of the disease by extracting the relevant cells from healthy and diseased tissue, studying the levels of proteins in the tissue and sequencing the RNA—the messenger that carries instructions from DNA for controlling the production of proteins.
Of the nine genes associated with osteoarthritis, researchers identified five genes in particular that differed significantly in their expression in healthy and diseased tissue. The five genes present novel targets for future research into therapies.

The joint first author said: "These results are an important step towards understanding the genetic causes of osteoarthritis and take us closer to uncovering the mechanism behind the disease. Once we know that, it opens the door to developing new therapies for this debilitating disease."

The team also explored genetic correlations between osteoarthritis and obesity, bone mineral density, type 2 diabetes, and raised blood lipid levels.

Researchers applied a statistical technique known as causal inference analysis to uncover which traits and diseases cause osteoarthritis, and which do not.

Within the limits of their study, scientists discovered that type 2 diabetes and high levels of lipids in the blood do not have causal effects on osteoarthritis, but reaffirm that obesity does.

The joint first author said: "Using genetic data, we have shown that type 2 diabetes and increased blood lipid levels do not appear to be on the causal path to osteoarthritis. We also reconfirmed that obesity is on the causal path to osteoarthritis."

Another researcher said: "The discovery of these genes is positive news for the 8.5 million people in the UK living with osteoarthritis. People living with this debilitating condition currently have limited treatment options. Meanwhile, they can struggle to do the day-to-day things most of us take for granted, like going to work or getting dressed independently. By revealing how these genes contribute to osteoarthritis, this research could open the door for new treatments to help millions of people live the pain free life they deserve."

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