Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson's disease
Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson's disease
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DOI：
10.1073/pnas.1901805116
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发表时间：
2019-07-30
影响因子：
11.1
通讯作者：
Schurr, Erwin
中科院分区：
文献类型：
--
作者：
Fava, Vinicius M.;Xu, Yong Zhong;Schurr, Erwin
1型反应（T1 R）是麻风病的病理性炎症发作，是神经损害的主要原因。在这里，我们评估了7个基因中罕见的蛋白质改变变体的基因富集，其中常见的变体以前与T1 R相关。我们选择了474名越南麻风患者，其中237名T1 R感染，237名T1 R免费匹配的对照。使用基于核的（序列核关联检验[SKAT]）和负荷方法检测非同义变体的基因富集。在测试的7个基因中，有2个显示出与T1 R相关的统计学证据。对于LRRK 2基因，在无T1 R对照中观察到非同义变体的富集（PSKAT-O = 1.6 x 10（-4））。这种基因关联几乎完全由功能获得性变体R1628 P驱动（P = 0.004;比值比= 0.29）。第二个基因关联是帕金编码基因PRKN（以前的PARK 2），其中7种罕见变异在T1 R感染病例中富集（PSKAT-O = 7.4 x 10（-5））。PRKN和LRRK 2的突变是帕金森病（PD）的已知原因。因此，我们评估了在T1 R中观察到的这种罕见氨基酸变化与PD共有的程度。我们观察到，Parkin中由非同义T1 R风险突变靶向的氨基酸也富集了与PD有关的突变（P = 1.5 x 10（-4））。因此，PD中的神经炎症和T1 R中由于炎症引起的外周神经损伤共享致病性的重叠遗传控制。
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 x 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 x 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 x 10(-4)). Hence, neuroinflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping genetic control of pathogenicity.