Fava Vinicius M, Manry Jérémy, Cobat Aurélie, Orlova Marianna, Van Thuc Nguyen, Ba Nguyen Ngoc, Thai Vu Hong, Abel Laurent, Alcaïs Alexandre, Schurr Erwin
Program in Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, Canada.
The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Canada.
PLoS Negl Trop Dis. 2016 Feb 4;10(2):e0004412. doi: 10.1371/journal.pntd.0004412. eCollection 2016 Feb.
Depending 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.
An 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.
A 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.
The 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.
根据流行病学情况，不同比例的麻风病患者会出现过度的促炎反应，称为1型反应（T1R）。LRRK2基因编码一种多功能蛋白，已被证明可调节促炎反应。在一些研究中，LRRK2基因附近的变异与麻风病有关，但在其他研究中并非如此。我们假设LRRK2是T1R易感性基因，不一致的关联结果可能反映了不同样本中T1R患者的不同比例。因此，我们评估了LRRK2变异与T1R易感性的关联。
使用156个单核苷酸多态性（SNP）对LRRK2基因座进行关联扫描。在两个基于家系的样本中评估关联证据：一组受T1R影响的家系和另一组无T1R的家系。只有相对于无T1R家系具有显著异质性证据且对受T1R影响的家系有显著意义的SNP才被视为T1R特异性。应用表达数量性状基因座（eQTL）分析来评估T1R特异性SNP对LRRK2基因转录水平的影响。
共检测到18个T1R特异性变异，分为4组。捕获T1R关联的核心SNP是LRRK2错义变异M2397T（rs3761863），它影响LRRK2蛋白周转。此外，一组与T1R相关的9个SNP在未刺激的全血细胞中是LRRK2的eQTL，但在暴露于麻风分枝杆菌抗原后不是。
结果支持LRRK2变异与T1R的优先关联。LRRK2参与T1R可能是由于由LRRK2可用性调节的病理性促炎环。有趣的是，M2397T变异与克罗恩病有关，其风险等位基因与T1R相同，表明这两种不同疾病存在共同的炎症机制。
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