Study Links Gene Variants to Crohn’s Disease and Parkinson’s Disease

Introduction to the Research

A recent study published in *Science Translational Medicine* explored the connection between gene variants associated with Crohn’s disease and Parkinson’s disease. Current treatments for inflammatory bowel diseases (IBD), such as Crohn’s disease (CD) and ulcerative colitis, often provide relief to only a small percentage of patients. Previous research has identified various genes linked to IBD, suggesting potential new therapeutic targets. However, these studies have largely concentrated on common gene forms, overlooking variant gene forms that can significantly impact gene functionality.

Methodology of the Study

To investigate gene variants affecting Crohn’s disease risk, researchers analyzed the genomes of 50 patients with full Ashkenazi Jewish ancestry, a group with a notably higher prevalence of IBD compared to non-Jewish Europeans. This analysis revealed 4,277 gene variants of interest. Subsequently, the genomes of 1,477 Ashkenazi Jewish patients with Crohn’s disease were compared to those of 2,614 individuals without the disease.

The genes showing the strongest associations with Crohn’s disease were further examined in a larger cohort consisting of 589 patients with the disease and 1,019 without it across North America, Europe, and Israel.

Key Findings on LRRK2 Variants

Among the identified genes, LRRK2 was highlighted, particularly its N551K variant, which was associated with a reduced risk of Crohn’s disease, while the N2081D variant was linked to an increased risk. Additionally, the K1423K and R1398H variants, previously shown to decrease Parkinson’s disease risk when paired with the N551K variant, were found to have only a minor impact on Crohn’s disease risk.

Further Analysis of LRRK2 Variants

The researchers then conducted an extensive analysis of Crohn’s disease risk related to LRRK2 variants using data from 8,314 Ashkenazi Jewish and 16,401 non-Jewish participants from other studies. This cohort included 6,538 individuals with Crohn’s disease, 5,570 with Parkinson’s disease, and 12,607 healthy participants. The gene products of the variants were evaluated in samples from 13 patients.

The N2081D variant was notably linked to an earlier onset of Crohn’s disease and its progression into the small intestine. The associated LRRK2-N2081D protein exhibited increased activity compared to other variants, resembling the LRRK2-G2019S protein associated with familial Parkinson’s disease. Furthermore, the N2081D variant was found to moderately elevate Parkinson’s disease risk, while the N551K variant slightly decreased it, albeit less significantly than its effect on Crohn’s disease.

Implications for Future Therapies

The findings from this study indicate that the N2081D and N551K variants of the LRRK2 gene could serve as promising targets for the development of new IBD therapies. Additionally, the results suggest shared mechanisms involving LRRK2 that may contribute to both Crohn’s disease and Parkinson’s disease. A deeper understanding of these mechanisms could advance treatment options for both conditions.

Conclusion

This study underscores the importance of examining gene variants in the context of Crohn’s disease and Parkinson’s disease, potentially paving the way for innovative therapeutic strategies.

Written by Raishard Haynes, MBS
Reference: Hul, K.Y. et al. (2018). Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci. Transl. Med. 10.1126/scitranslmed.aai7795