Wu Yih-Ru, Chang Kuo-Hsuan, Chang Wen-Teng, Hsiao Ya-Chin, Hsu Hsuan-Chu, Jiang Pei-Ru, Chen Yi-Chun, Chao Chih-Ying, Chang Yi-Chung, Lee Bo-Hsun, Hu Fen-Ju, Chen Wan-Ling, Lee-Chen Guey-Jen, Chen Chiung-Mei
Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
PLoS One. 2013 Dec 5;8(12):e82001. doi: 10.1371/journal.pone.0082001. eCollection 2013.
Genetic variants of leucine-rich repeat kinase 2 (LRRK2) were reported to alter the risk for Parkinson's disease (PD). However, the genetic spectrum of LRRK2 variants has not been clearly disclosed yet in Taiwanese population. Herein, we sequenced LRRK2 coding region in 70 Taiwanese early onset PD patients (age at onset ≤ 50), and found six amino acid-changing single nucleotide polymorphisms (SNPs, N551K, R1398H, R1628P, S1647T, G2385R and M2397T), one reported (R1441H) and 2 novel missense (R767H and S885N) mutations. We examined the frequency of identified LRRK2 variants by genotyping 573 Taiwanese patients with PD and 503 age-matched control subjects. The results showed that PD patients demonstrated a higher frequency of G2385R A allele (4.6%) than control subjects (2.1%; odds ratio = 2.27, 95% confidence interval: 1.38-3.88, P = 0.0017). Fewer PD patients (27.7%) carried the 1647T-2397T haplotype as compared with the control subjects (33.0%; odds ratio = 0.80, 95% confidence interval: 0.65-0.97, P = 0.0215). However, the frequency of 1647T-2385R-2397T haplotype (4.3%) in PD patients was still higher than in control subjects (1.9%, odds ratio: 2.15, 95% confidence interval: 1.27-3.78, P = 0.0058). While no additional subject was found to carry R767H and R1441H, one more patient was observed to carry the S885N variant. Our results indicate a robust risk association regarding G2385R and a new possible protective haplotype (1647T-2397T). Gene-environmental interaction and a larger cohort study are warranted to validate our findings. Additionally, two new missense mutations (R767H and S885N) regarding LRRK2 in PD patients were identified. Functional studies are needed to elucidate the effects of these LRRK2 variants on protein function.
据报道，富含亮氨酸重复激酶2（LRRK2）的基因变异会改变帕金森病（PD）的发病风险。然而，台湾人群中LRRK2变异的基因谱尚未明确揭示。在此，我们对70名台湾早发性PD患者（发病年龄≤50岁）的LRRK2编码区进行了测序，发现了6个导致氨基酸改变的单核苷酸多态性（SNP，N551K、R1398H、R1628P、S1647T、G2385R和M2397T），1个已报道的（R1441H）以及2个新的错义（R767H和S885N）突变。我们通过对573名台湾PD患者和503名年龄匹配的对照受试者进行基因分型，检测了已鉴定的LRRK2变异的频率。结果显示，PD患者中G2385R A等位基因的频率（4.6%）高于对照受试者（2.1%；优势比=2.27，95%置信区间：1.38 - 3.88，P = 0.0017）。与对照受试者（33.0%）相比，携带1647T - 2397T单倍型的PD患者较少（27.7%；优势比=0.80，95%置信区间：0.65 - 0.97，P = 0.0215）。然而，PD患者中1647T - 2385R - 2397T单倍型的频率（4.3%）仍高于对照受试者（1.9%，优势比：2.15，95%置信区间：1.27 - 3.78，P = 0.0058）。虽然未发现其他携带R767H和R1441H的受试者，但观察到有1名患者携带S885N变异。我们的结果表明G2385R存在显著的风险关联以及一种新的可能具有保护作用的单倍型（1647T - 2397T）。基因 - 环境相互作用以及更大规模的队列研究有必要来验证我们的发现。此外，在PD患者中鉴定出了两个关于LRRK2的新错义突变（R767H和S885N）。需要进行功能研究以阐明这些LRRK2变异对蛋白质功能的影响。
