Image: The BD FACS CANTO II multiparameter flow cytometer (Photo courtesy of BD Biosciences).
The inflammatory bowel diseases (IBD) are composed of two major subtypes, Crohn’s disease (CD) and ulcerative colitis (UC), which are distinguished by the distribution of chronic inflammatory changes.
In UC, the inflammation is relatively superficial and is confined to the colon. CD most commonly affects the terminal ileum (last part of the small intestine) and colon and is frequently associated with deep, transmural inflammation, often resulting in obstruction and abscess formation requiring resectional surgery.
A large team of scientists led by those at Yale University School of Medicine, New Haven, CT USA) performed exome sequencing of 50 Ashkenazi Jewish individuals with CD (44 independent individuals and three full-sibling pairs). They selected 4,277 putatively high-yield new mutations that were added to the base content of the Illumina HumanExome 1.0 array to create a semicustom genotyping platform. With this, they performed discovery-phase genotyping and association analyses in 1,477 CD cases and 2,614 controls with full genetic Ashkenazi Jewish ancestry. Macrophages from CD patients were derived from whole peripheral blood monocytes, probed and analyzed on a CANTO II multiparameter flow cytometer.
The scientists identified mutations in the leucine rich repeat kinase 2 (LRRK2) gene that are more frequently found in Crohn's disease cases as compared to unaffected individuals. When they discovered a link between Crohn's and the LRRK2 gene mutations they went further to assess the possible genetic link between Crohn's and Parkinson's. The team then looked at a much larger sample of 24,570 people including patients with Crohn's, Parkinson's, and no disease at all (each group consisted of Jewish and non-Jewish subjects).
The team found two mutations of the LRRK2 gene in Crohn's disease patients. One of them (called the risk mutation) was more common in patients with Crohn's, while the other (the protective mutation) was more prevalent in patients without the disease. Most Crohn's disease patients who carried the risk mutation developed the disease on average six years earlier than those who did not carry this mutation. The study also shows that more Crohn's patients with the risk mutation developed the disease in the small intestine, compared to those without the mutation.
Inga Peter, PhD, a Professor of Genetics and a lead investigator of the study, said, “Crohn's disease is a complex disorder with multiple genes and environmental factors involved, which disproportionally affects individuals of Ashkenazi Jewish ancestry. The presence of shared LRRK2 mutations in patients with Crohn's disease and Parkinson's disease provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.” The study was published on January 10, 2018, in the journal Science Translational Medicine.
Yale University School of Medicine