Crohn’s and Parkinson’s diseases seem to share a common genetic risk pathway, mediated by mutations in a gene that modify disease risk in both directions.
A multidisciplinary collaboration of researchers have discovered that the Crohn’s risk variant N2081D in the leucine-rich repeat kinase 2 (LRRK2) gene lies close to variant G2019S, the major genetic risk factor for both sporadic and familial Parkinson’s. However, protective mutations also occur in the LRRK2 gene, and Ken Y. Hui, MD, of Yale University, New Haven, Conn., and his associates identified two that, when combined, significantly decrease the risk of Crohn’s.
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The team first discovered the association in an exome sequencing study of 50 Crohn’s patients of Ashkenazi Jewish descent. This identified more than 4,000 potentially high-yield mutations, which they then examined in a pure Ashkenazi cohort of 1,477 Crohn’s patients and 2,614 healthy controls.
In this phase, the researchers found that N2081D in LRRK2 was associated with a 73% increased odds of Crohn’s. The LRRK2 N551K variant was associated with protection against Crohn’s, reducing odds for the disease by 35% (odds ratio, 0.65), as was R1398H, which conferred a 29% reduction in the likelihood of developing the disease (OR, 0.71). It has been known that these two mutations can combine to provide a protective genetic signature, and the team investigated this compound interaction as well.
After repeated analyses in large, unique case-control cohorts and tissue samples, they determined that the N2081D allele increased the odds of Crohn’s by 70% in the Ashkenazi subjects and by 60% in non-Ashkenazi subjects. The allele was associated with a 10% increased likelihood of Parkinson’s among the Ashkenazi cohort and a 30% increased likelihood among the non-Ashkenazi cohort.
The researchers also examined the two protective alleles, N551K and R1398H, in these further analyses. In the Ashkenazi cohort, N551K decreased the likelihood of Crohn’s by 33%, and it decreased the likelihood of Parkinson’s by 23% in non-Ashkenazi subjects (OR, 0.67 and 0.77, respectively).
In the Ashkenazi cohort, R1398H reduced the odds of Crohn’s by 29% and the odds of Parkinson’s by 16% (OR, 0.71 and 0.84, respectively). In the non-Ashkenazi cohort, the risk reduction was not significant.
Finally, they examined the effect of the mutations on macrophages isolated from four Crohn’s patients who carried the N2081D allele, as well as five patients with the two protective mutations N551K and R1398H and four patients with no mutation. When the macrophages were put in nutrient starvation, those from the N2081D carriers exhibited impaired resting acetylation of alpha-tubulin and poor response to cellular stress. Decreased alpha-tubulin acetylation is associated with poor protein transport through the cytoskeleton. “In contrast, the highest basal acetylation of alpha-tubulin was detected in macrophages of noncarriers and carriers of the protective N551K + R1398H mutations,” the investigators wrote.
“Our study strongly implicates the contribution of LRRK2 in Crohn’s disease risk,” they concluded. “The LRRK2 N2081D risk allele and the N551K/R1398H protective alleles, as well as numerous other variants within the LRRK2 locus, revealed shared genetic effects between Crohn’s and Parkinson’s risk, providing a potential biological basis for clinical co-occurrence. Our findings suggest that LRRK2 may be a useful target for developing drugs to treat Crohn’s disease.”
The research was supported by a variety of grants from the National Institutes of Health, the National Science Foundation, and various other foundations. Five of the authors reported consulting for various pharmaceutical companies or companies selling genetic information products. None of the other authors had relevant disclosures.
SOURCE: Hui K et al. Sci Transl Med. 2018. doi: 10.1126/scitranslmed.aai7795
