A new study overthrows the widely held notion that the primary cilium is an organelle important only during development and in rare diseases, and reveals distinct roles for sub-compartments of this curious and ubiquitous organelle in common diseases, such as diabetes, kidney failure, and liver fibrosis—pointing to a potential way to treat or even cure them.
Unlike the copious hair-like cilia associated with movement in specialized cells such as those lining our trachea, the primary cilium is a small, immovable projection of the cell’s surface that acts like an antenna. It is found on nearly every human cell type.
Scientists at the University of Pennsylvania and the Children’s Hospital of Philadelphia performed association studies of 16,874 common genetic variants across 122 ciliary genes with 12 quantifiable laboratory traits characteristic of diseases affecting primary cilia (ciliopathy syndromes) in 452,593 individuals in the UK Biobank and identified 101 significant associations with 42 ciliary genes.
These findings are published in the American Journal of Human Genetics article, “Mendelian pathway analysis of laboratory traits reveals distinct roles for ciliary subcompartments in common disease pathogenesis.”
“One of the most exciting implications of our study is that the cilium may represent a common therapeutic target since it appears to be involved in a number of complex diseases,” says Theodore Drivas, MD, PhD, a postdoctoral fellow in the lab of Marylyn Ritchie, PhD, professor of genetics and director of the Center for Translational Bioinformatics, clinical associate in Internal Medicine and lead author on the study. “The cilium has not before been considered as a therapeutic target for drug development for common diseases. It’s an interesting prospect.”
The UK Biobank is a research database that includes electronic health records and genetic information. “Resources like the UK Biobank provide enormous potential to link genes related to rare diseases with common diseases and traits”, said Ritchie.
The authors establish 42 of the 122 ciliary gene examined are strongly associated with diabetes, kidney failure, liver disease, and high cholesterol levels within blood samples the team examined. Bioinformatic and genomic analyses demonstrated these associations are not restricted to rare genetic variants but are tied to some of the more common ones as well.
“These genes were found to be widely expressed across all human tissues, with our data suggesting that genetically-encoded changes in the degree to which these genes are activated might be behind their involvement in common disease development,” says Drivas. “Our findings challenge the widely-held belief that the cilium is an organelle important mainly in rare genetic syndromes and suggest that they could also be behind many common diseases that have yet to be cured.”
The novel link between primary cilia and common genetic diseases opens the possibility of new drug targets in the primary cilium, and potential gene therapies for many common conditions.
Diabetes affects more than 34 million people in the United States, which accounts for more than 10% of the population, with many only able to control it via insulin injections. New therapies, driven by a patient’s genetics, could provide much more targeted and effective treatments for patients with diabetes.
Before novel therapeutics can be developed based on these new findings, the team plans to validate these discoveries in cellular models.
“Ultimately we hope to use these findings to screen libraries of small molecules to identify drugs that might help modulate ciliary function and which might have the potential to treat some of the diseases we examined in our study,” says Drivas.
“The potential to use this study as a model for exploring other rare disease genes is exciting,” says Ritchie. “There could be many more genes we think of as causal for rare disease that are also important for common disease risk as well.”