Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 31; pp. 15616 - 15624
• Main Authors: Fava, Vinicius M., Xu, Yong Zhong, Lettre, Guillaume, Van Thuc, Nguyen, Orlova, Marianna, Thai, Vu Hong, Tao, Shao, Croteau, Nathalie, Eldeeb, Mohamed A., MacDougall, Emma J., Cambri, Geison, Lahiri, Ramanuj, Adams, Linda, Fon, Edward A., Trempe, Jean-François, Cobat, Aurélie, Alcaïs, Alexandre, Abel, Laurent, Schurr, Erwin
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30.07.2019
• Series: PNAS Plus
• Subjects: Amino acid sequence; Amino acids; Biological Sciences; Damage assessment; Enrichment; Female; Genes; Genetic control; Humans; Inflammation; Kernels; Leprosy; Leprosy - genetics; Leprosy - metabolism; Leprosy - pathology; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; LRRK2 protein; Male; Movement disorders; Mutation; Neural coding; Neurodegenerative diseases; Parkin protein; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathogenicity; Pathogens; Peripheral nerves; PNAS Plus; Test procedures; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; leprosy type-1 reaction; inflammation; LRRK2; Parkinson’s disease; Parkin
• DOI: 10.1073/pnas.1901805116
• ISSN: 0027-8424

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 (P SKAT-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 (P SKAT-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.