It isn’t exactly earth-shaking news that a number of inflammatory diseases, including Crohn’s disease and ulcerative colitis, commonly occur together in individuals and families. Also, it has long been suspected that these inflammatory processes emanate from a shared fault, either environmental or genetic. But now, thanks to a global survey, the subterranean connection has finally been revealed. It is mainly genetic.
The genetic substratum for the five diseases—ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis, and primary sclerosing cholangitis—was unearthed in a study that was led by scientists from Queensland University of Technology (QUT), Brisbane, Australia, and Christian-Albrechts-University, Kiel, Germany. These scientists, who pieced together information provided by 50 different research centers from around the world, ultimately determined that the five diseases have common genetic ground, and that the ground consists of hundreds of genes.
The details appeared March 14 in the journal Nature Genetics, in an article entitled, “Analysis of Five Chronic Inflammatory Diseases Identifies 27 New Associations and Highlights Disease-Specific Patterns at Shared Loci.” The article describes how the researchers combined Immunochip genotype data for 52,262 cases and 34,213 controls of European ancestry, drawing from what are “currently the largest available genetic data sets in five clinically related seronegative immune-driven phenotypes,” to explore the extent of sharing of genetic susceptibility loci.
“Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci,” wrote the study’s authors. “Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat, and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity.”
According to Matthew Brown, M.D., a co-senior author of the study and a professor at QUT's Institute of Health and Biomedical Innovation, the new gene discoveries pointed to some potential new therapies, including agents already in use for other diseases which can now be trialed in these conditions very promptly.
"The discoveries have shed new light onto the causes of these diseases, such as identifying genetic risk variants which most likely work by affecting the bacteria present in the gut, in turn causing inflammation in joints, the liver or the gut itself," noted Professor Brown. "These study findings are a major leap forward in our understanding of these common but difficult-to-treat diseases.”
The diseases affect about 3% of the world's population and are often debilitating and difficult to treat. That these diseases could be traced to shared genetic risk factors, rather than found to give rise to each other, lends credence to the study’s overall approach—looking across the genetics of multiple diseases to resolve overlapping associations into discrete pathways, and to explore details of apparently shared etiologies.
"It has been known for over 50 years these conditions frequently occur together in individuals and families. We now know this is mainly because the genes involved affect the risk of many diseases, and that the diseases are therefore very similar in their underlying causes, even if they present in such different ways,” concluded Professor Brown. "This research has pointed us to several different potential therapeutic targets for these diseases, for which there is a huge global need for better therapies."