Research Article: A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy

Date Published: February 4, 2016

Publisher: Public Library of Science

Author(s): Vinicius M. Fava, Jérémy Manry, Aurélie Cobat, Marianna Orlova, Nguyen Van Thuc, Nguyen Ngoc Ba, Vu Hong Thai, Laurent Abel, Alexandre Alcaïs, Erwin Schurr, Christian Johnson.

Abstract: BackgroundDepending on the epidemiological setting, a variable proportion of leprosy patients will suffer from excessive pro-inflammatory responses, termed type-1 reactions (T1R). The LRRK2 gene encodes a multi-functional protein that has been shown to modulate pro-inflammatory responses. Variants near the LRRK2 gene have been associated with leprosy in some but not in other studies. We hypothesized that LRRK2 was a T1R susceptibility gene and that inconsistent association results might reflect different proportions of patients with T1R in the different sample settings. Hence, we evaluated the association of LRRK2 variants with T1R susceptibility.MethodologyAn association scan of the LRRK2 locus was performed using 156 single-nucleotide polymorphisms (SNPs). Evidence of association was evaluated in two family-based samples: A set of T1R-affected and a second set of T1R-free families. Only SNPs significant for T1R-affected families with significant evidence of heterogeneity relative to T1R-free families were considered T1R-specific. An expression quantitative trait locus (eQTL) analysis was applied to evaluate the impact of T1R-specific SNPs on LRRK2 gene transcriptional levels.Principal FindingsA total of 18 T1R-specific variants organized in four bins were detected. The core SNP capturing the T1R association was the LRRK2 missense variant M2397T (rs3761863) that affects LRRK2 protein turnover. Additionally, a bin of nine SNPs associated with T1R were eQTLs for LRRK2 in unstimulated whole blood cells but not after exposure to Mycobacterium leprae antigen.SignificanceThe results support a preferential association of LRRK2 variants with T1R. LRRK2 involvement in T1R is likely due to a pathological pro-inflammatory loop modulated by LRRK2 availability. Interestingly, the M2397T variant was reported in association with Crohn’s disease with the same risk allele as in T1R suggesting common inflammatory mechanism in these two distinct diseases.

Partial Text: Leprosy is a chronic dermato-neurological infectious disease caused by M. leprae. Leprosy irrespective of its clinical presentation is curable by multi-drug therapy. The current global effort in leprosy control is focused on early recognition of leprosy cases and prevention of permanent disabilities [1]. A common complication of leprosy are excessive pro-inflammatory episodes termed type-1 reactions (T1R) [2]. If untreated, T1R can lead to irreversible nerve function impairment due to a pathological cellular immune response directed against host peripheral nerve cells [3]. Up to 50% of all leprosy cases can undergo T1R with the incidence varying according to endemic settings and criteria for case definition [4].

We identified an amino acid change M2397T in the WD40 domain of LRRK2 and a bin tagged by the variant the variant rs1031996 as being associated specifically with T1R. LRRK2 is a protein that exerts a diverse set of functions. LRRK2 mediates catalytic processes through its enzymatic ROC/COR domain; facilitates signal transduction through a MAPK domain and interacts with other proteins through three scaffold domains, an ankylin repeat (ANK), a leucine rich repeat (LRR) and a WD40 repeat domain [33]. Scaffold domains are also responsible for protein conformation and stability [33]. Although, LRRK2 displays multiple functions, the association of T1R with a variant in the WD40 domain of LRRK2 suggests that protein conformation and/or stability are key factors in T1R. Indeed, the M2397T variant in LRRK2 has previously been shown to impact on LRRK2 protein turnover [34]. The half-life of LRRK2 with the T1R-risk allele M2397 had been estimated at approximately 8 hrs which is substantially shorter than the estimated 18 hrs half-life of the T2397 allele of LRRK2 (Fig 4) [34]. Cytoplasmic LRRK2 forms a complex that arrests nuclear factor of activated T-cells (NFAT) in the cytoplasm [34]. A consequence of LRRK2 deficit in the cytoplasm is the translocation of NFAT to the nucleus, which strongly induces the transcription of pro-inflammatory cytokines (Fig 4) [35, 36]. Thus, the association of the M2397 allele with T1R-risk is in agreement with an exacerbated pro-inflammatory response in T1R cases (Fig 4). While the M2397T variant is a strong candidate for functional impact in T1R, the association of the bin tagged by rs1031996 requires further investigations.



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