One gene (LRRK2) associated with two very different diseases, Crohn disease and Parkinson disease

Crohn disease (CD) and ulcerative colitis are distinguished by the distribution of chronic inflammatory changes. In ulcerative colitis, 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 inflammation that invades the intestinal wall, often resulting in obstruction and abscess formation requiring resectional surgery. Approved medical therapies for moderate to severe CD and ulcerative colitis and include monoclonal antibodies against the proinflammatory tumor necrosis factor (TNF) cytokine and, more recently, antibodies against a4b7 integrin, which blocks leukocyte-trafficking to the intestine. Monoclonal antibodies blocking the interleukin-23 pathway have also shown efficacy in inflammatory bowel diseases.

Authors [see attached] hypothesized that uncommon CD-susceptibility high-effect alleles (i.e. larger odds ratios; ORs), which had eluded analysis in common variant-predominant genome-wide association studies (GWAS), might play an important role in genetic predisposition to CD. They sought to identify the strongest functionally relevant associations and to characterize their biological implications. Given that a major epidemiological feature of inflammatory bowel diseases is its several-fold higher prevalence in Ashkenazi Jewish cohorts, compared to non-Jewish Europeans, authors performed whole-exome sequencing (WES( of Ashkenazi Jewish CD cases, followed by custom array–based genotyping in a large case-control cohort.

Authors identified independent coding CD risk and protective alleles in LRRK2, a large multifunctional gene (encoding leucine-rich repeat kinase-2) that confers the greatest genetic effects reported thus far in Parkinson disease (PD), a neurodegenerative movement disorder affecting the basal ganglia and characterized by resting tremor, bradykinesia, rigidity, and postural instability. Presence of shared alleles in CD and PD provides refined insight into disease mechanisms that may have major implications for the treatment of these two seemingly unrelated diseases. In human genetics, this is an example of PLEIOTROPY –– when one gene will encode, and control, the phenotype or expression of several different and unrelated traits (in this case, CD in the bowel and PD in the brain).

Sci Transl Med 10: eaai7795 (10 Jan 2018)

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