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Large Genomic Study Finds New Rheumatoid Arthritis Targets

Hands with arthritis (NIH)

(National Institutes of Health)

An international consortium of 70 institutions and companies combined genome-wide analyses with current drug databases to uncover new genomic targets for rheumatoid arthritis, and identify drugs for other diseases with the potential to treat the disorder. The team led by Robert Plenge of Harvard Medical School and the Broad Institute and Yukinori Okada from the RIKEN Center for Integrative Medical Sciences in Japan published its findings online yesterday in the journal Nature (paid subscription required).

Rheumatoid arthritis is an auto-immune disorder where the immune system is tricked into attacking the body’s own tissues. In this case, the disease results in painful inflammation and swelling of the lining of small joints in the hands and feet that can lead to bone erosion and joint deformity.

About 0.5 to 1.0 percent of adults in developing countries are believed to have rheumatoid arthritis, including about 1.5 million people in the U.S., according to the Arthritis Foundation. The disorder most commonly begins between the ages of 30 and 60, and affects three times as many women as men.

While whole-genome analysis has been used previously to identify genes contributing to disease, the authors say this is the first large-scale genomic analysis to be coupled with queries of other biological and drug databases, as well as bioinformatics, to identify new therapy targets and discover new drugs. This approach, say the authors, appears suited for rheumatoid arthritis and other complex diseases. Many earlier whole-genome studies are based on single population groups, while this new study cuts across ethnic groups.

Plenge, Okada, and colleagues conducted a genome-wide meta-analysis of more than 100,000 subjects — about 30,000 with rheumatoid arthritis and nearly 74,000 controls — combining those of European and Asian origins. The team analyzed some 10 million genetic variations known as single nucleotide polymorphisms, the most common genetic  variant that often serve as biological markers for disease.

The analysis yielded 42 new regions in the genome associated with rheumatoid arthritis; 59 regions were previously linked to the disease, raising the total to 101. In addition, the researchers identified 98 genes in the 101 genomic regions as biological candidates for the disease, using a combination of bioinformatics and genetic analysis techniques.

The bioinformatics results highlighted not only targets for new drugs, but also potential uses for current drugs on the market to treat conditions not normally related to rheumatoid arthritis. The team ran the genomic findings against existing drug databases, which showed many of the 98 candidate genes overlapped with regions targeted by existing drugs for rheumatoid arthritis, although in some cases, these overlaps were not known before the study.

The researchers also discovered current drugs in development to treat cancer with potential as therapies for rheumatoid arthritis, such as inhibitors that target the CDK4 and CDK6 cell cycle pathways associated with blood cancers, e.g., mantle cell lymphoma. The findings point to possibly more overlaps of genes associated with rheumatoid arthritis, immunodeficiency disorders, and blood cancers.

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