Study highlights key players in autoimmune disease
By Nicole Davis, Broad Communications
With the new meta-analysis, 11 genetic risk factors have now been linked to rheumatoid arthritis, an autoimmune disorder.
Image courtesy of Bang Wong
The immune system is indeed a critical ally, a staunch defender against disease. Yet when its ferocity is unleashed on the very things it should protect, namely the body's organs and tissues, it morphs into an unwitting adversary. The genes that underpin this so-called autoimmunity have now come into clearer view, thanks to a new study of rheumatoid arthritis, a disease in which turncoat immune cells attack the joints as well as other vital tissues, such as the lungs, skin and blood vessels.
Bringing the power of genomics to bear on the disease, an international team of researchers pooled their resources and expertise to analyze data from three recent genome-scale studies of rheumatoid arthritis. The results of this meta-analysis highlight several novel genes associated with the disease and underscore a key molecular pathway that may offer promise in the design of future therapies. The findings are published in the September 14 advance online edition of Nature Genetics.
"Through a remarkable collaborative effort, we have identified six novel gene regions that are associated with risk of rheumatoid arthritis," said senior author Robert Plenge, a researcher at the Broad Institute of MIT and Harvard who is also an assistant professor at Harvard Medical School and director of genetics and genomics in the Division of Rheumatology, Immunology and Allergy at Brigham and Women's Hospital. "Perhaps the most striking result to emerge is that the CD40 pathway seems to be one of the critical linchpins in this disease, suggesting its relevance as a therapeutic target."
Rheumatoid arthritis affects about 1% of the adult population worldwide. Effective treatments are available, but as many as one-third of patients receive little or no relief from them. As with many common diseases, a major stumbling block to new therapies has been the lack of basic knowledge about the disease's root causes.
Scientists have long recognized that genetics plays a role in rheumatoid arthritis, yet for years, only two genes were convincingly linked to the disease. Last year, that number more than doubled with the publication of three independent studies, all of them grounded in an approach known as genome-wide association (GWA). The method has recently been applied to a variety of other diseases and involves quickly scanning for single-letter DNA differences that occur more frequently in the genomes of people who have a particular disease than in those who do not. By drawing these genetic associations, scientists were able to pinpoint regions in the genome, and even identify specific genes, that likely play roles in rheumatoid arthritis.
Convinced there are still many other culprit genes yet to be found, and that pooling existing data can help unearth these genes, Plenge and his colleagues - including first author and post-doctoral research fellow Soumya Raychaudhuri and Broad senior associate member Mark Daly - combined and further analyzed data from three published GWA studies of rheumatoid arthritis. This work unearthed more than 30 promising genetic associations, which the researchers sought to validate through subsequent studies of eight independent patient sample collections, including one based at the Brigham and Women's Hospital (known as the Brigham Rheumatoid Arthritis Sequential Study or BRASS). Researchers in the Broad's Genetic Analysis Platform provided expertise to help complete this critical phase of the study.
From their stepwise analysis, the researchers pinpointed six new genes or genetic regions with links to rheumatoid arthritis, bringing the total number of genes known to be involved in the disease from 5 to 11. The most robust of these associations is a single-letter change, known as a single nucleotide polymorphism or SNP, within the CD40 gene, which normally acts to transmit key signals from the surfaces of a variety of immune cells. Earlier genomic work on rheumatoid arthritis had implicated two genes that function together with CD40 to relay molecular signals. Taken together, the results provide tantalizing evidence that this signaling pathway is important in rheumatoid arthritis.
Interestingly, the CD40 pathway has previously been the focus of drug-related research, but the work was later abandoned for toxicity reasons. Plenge said he hopes the team's results will reinvigorate interest in the pathway.
In addition to the CD40 results, the researchers' other findings also implicate a variety of immune genes. For example, the second most strongly associated SNP lies near a gene, called CCL21, that helps immune cells home in on sites of injury or infection throughout the body. And the four remaining SNPs, though more weakly associated with rheumatoid arthritis than the other two, also lie within or near genes with immune-related functions.
"As of today, we think we can explain about one-third of the genetic risk of rheumatoid arthritis," said Plenge. But, he also noted that despite the vast amount of data dedicated to the current study, the work was still underpowered, statistically speaking. That means the genomic pot must be expanded even further - more patients and their DNA are needed for analysis - in order to ferret out the majority of the genes involved in rheumatoid arthritis.
Indeed, the work stands as a shining example of both the great strides that researchers have taken to understand the biological basis of the disease as well as the ground that remains to be covered before that understanding is fully complete.
Other Broad Institute researchers who contributed to the rheumatoid arthritis study include: Rachel Hackett, Candace Guiducci, Noel Burtt, Lauren Gianniny, Sandra Wong, Benjamin Neale, Kristin Ardlie, and David Altshuler.