Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson's disease
Autor: | Linda B. Adams, Yong Zhong Xu, Jean-François Trempe, Ramanuj Lahiri, Vu Hong Thai, Aurélie Cobat, Guillaume Lettre, Vinicius M. Fava, Nathalie Croteau, Shao Tao, Marianna Orlova, Mohamed A. Eldeeb, Erwin Schurr, Alexandre Alcaïs, Geison Cambri, Edward A. Fon, Laurent Abel, Nguyen Van Thuc, Emma J. MacDougall |
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Rok vydání: | 2019 |
Předmět: |
Nonsynonymous substitution
Male Parkinson's disease Ubiquitin-Protein Ligases Disease Biology Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Parkin 03 medical and health sciences Immunology and Inflammation 0302 clinical medicine Leprosy medicine leprosy type-1 reaction Humans Letters Gene 030304 developmental biology LRRK2 Gene Genetics 0303 health sciences Multidisciplinary LRRK2 Parkinson Disease Odds ratio Biological Sciences medicine.disease nervous system diseases 3. Good health PNAS Plus inflammation Mutation Parkinson’s disease Female 030217 neurology & neurosurgery |
Zdroj: | Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America |
ISSN: | 1091-6490 |
Popis: | Significance Type-1 reactions (T1R) are pathological immune responses in leprosy and a frequent cause of peripheral nerve damage. Employing a candidate gene approach combined with deep resequencing, we identified amino acid mutations in the E3 ligase Parkin and the polyfunctional kinase LRRK2 that were associated with T1R. This finding directly linked both proteins with the extent of the immune response in an infectious disease. Moreover, amino acids associated with T1R mutations were significantly enriched for mutations found in patients suffering from Parkinson’s disease (PD). These findings confirm Parkin and LRRK2 as 2 key inflammatory regulators and suggest that T1R and PD share overlapping pathways of pathogenesis. Type-1 reactions (T1R) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the genewise enrichment of rare protein-altering variants in 7 genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy patients of which 237 were T1R-affected and 237 were T1R-free matched controls. Genewise enrichment of nonsynonymous variants was tested with both kernel-based (sequence kernel association test [SKAT]) and burden methods. Of the 7 genes tested 2 showed statistical evidence of association with T1R. For the LRRK2 gene an enrichment of nonsynonymous variants was observed in T1R-free controls (PSKAT-O = 1.6 × 10−4). This genewise association was driven almost entirely by the gain-of-function variant R1628P (P = 0.004; odds ratio = 0.29). The second genewise association was found for the Parkin coding gene PRKN (formerly PARK2) where 7 rare variants were enriched in T1R-affected cases (PSKAT-O = 7.4 × 10−5). Mutations in both PRKN and LRRK2 are known causes of Parkinson’s disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that amino acids in Parkin targeted by nonsynonymous T1R-risk mutations were also enriched for mutations implicated in PD (P = 1.5 × 10−4). Hence, neuroinflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping genetic control of pathogenicity. |
Databáze: | OpenAIRE |
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