MultipleLRRK2variants modulate risk of Parkinson disease: a Chinese multicenter study

Abstract

We and others found two polymorphic LRRK2 (leucine-rich repeat kinase 2) variants (rs34778348:G>A; p.G2385R and rs33949390:G>C; p.R1628P) associated with Parkinson disease (PD) among Chinese patients, but the common worldwide rs34637584:G>A; p.G2019S mutation, was absent. Focusing exclusively on Han Chinese, we first sequenced the coding regions in young onset and familial PD patients and identified 59 variants. We then examined these variants in 250 patients and 250 control subjects. Among the 17 polymorphic variants, five demonstrated different frequency in cases versus controls and were considered in a larger sample of 1,363 patients and 1,251 control subjects. The relative risk of an individual with both p.G2385R and p.R1628P is about 1.9, and this is reduced to 1.5-1.6 if the individual also carries rs7133914:G>C; p.R1398H or rs7308720:C>A: p.N551K. The risk of a carrier with p.R1628P is largely negated if the individual also carries p.R1398H or p.N551K. In dopaminergic neuronal lines, p.R1398H had significantly lower kinase activity, whereas p.G2385R and p.R1628P showed higher kinase activity than wild type. We provided the first evidence that multiple LRRK2 variants exert an individual effect and together modulate the risk of PD among Chinese.

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

“…The R1398H LRRK2 polymorphism is quite common (>5 %) in several populations and apparently plays a protective role against development of PD [102,[106][107][108][109]. The R1398 residue is located in the switch II motif of the ROC domain and could be important for the interaction with the γ-phosphate of GTP [87].…”

LRRK2 A419V variant is a risk factor for Parkinson's disease in Asian population

“…Before Ross et al study, there have been 4 articles exploring the associations between A419V and PD, yet none of them showed the p-value < 0.05 (Di Fonzo et al, 2006;Jasinska-Myga et al, 2010;Nuytemans et al, 2009;Tan et al, 2010). The total number of Asian PD patients and controls in Ross et al study is large but when dividing the number into 3 different countries, it is much smaller: Taiwan, 369 PD patients; South Korea, 830 PD patients; Japan, 177 PD patients.…”

“…However, a lot of replications showed controversial results (Di Fonzo et al, 2006;Gopalai et al, 2013;Li et al, 2012;Tan et al, 2010;Wu et al, 2012;Wu-Chou et al, 2013). Herein, we conducted a case-control study to explore the potential associations between A419V and PD in Chinese population and conducted a meta-analysis centering on Asian population.…”

“…Furthermore, we reviewed the reference lists from retrieved articles to search for more studies. Following criteria were used to identify relevant studies for the meta-analysis: (1) Clinical diagnosis of PD Gopalai et al, 2013;Heckman et al, 2013;Jasinska-Myga et al, 2010;Li et al, 2012;Nuytemans et al, 2009;Ross et al, 2011;Tan et al, 2010;Wu et al, 2012;Wu-Chou et al, 2013). We extracted the following data from each publication: the first author's name, the publication year, population studied, the frequency of the LRRK2 A419V variant among PD patients, and the controls group (Table 1).…”

Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant Parkinson's disease

“…16,17,[34][35][36][37][38][39] One of these studies included 26 patients with a familial history of PD, among which six patients were p.G2385R carriers. 40 A meta-analysis on the basis of these studies involving 2205 PD patients and 1817 controls demonstrated average carrier rates of 9.3% in PD and 4% in controls.…”