Yu Wen-Juan, Cheng Lan, Li Nan-Nan, Wang Ling, Tan Eng-King, Peng Rong
Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, PR China.
Duke-NUS Graduate Medical School, Singapore, Singapore.
eNeurologicalSci. 2015 Aug 7;1(1):3-6. doi: 10.1016/j.ensci.2015.08.001. eCollection 2015 Mar.
PD is a complex disease, and may result from gene-gene and gene-environment interactions. There are limited studies on gene-gene interactions in PD. We and others have previously shown that SNCA rs356219, LRRK2 (rs2046932 and rs7304279) and GAK (rs1564282) are risk factors in sporadic PD. Since the expression of SNCA and neurotoxicity of alpha-synuclein are affected by LRRK2 and GAK, we hypothesize that their genetic risk variants may interact with each other. Here we investigated the interaction of SNCA rs356219, LRRK2rs7304279 and rs2046932 and GAK rs1564282 using the Multifactor Dimensionality Reduction (MDR) in a Chinese PD patient-control series (534 patients and 435 controls) and the cumulative risk effect of SNCA, LRRK2 and GAK. The MDR analysis showed a significant gene-gene interaction between the rs356219 of SNCA, rs2046932 of LRRK2 and rs1564282 of GAK. Moreover, individuals with increasing numbers of variants had an increasing likelihood of having PD, compared with those carrying none of the variants. The estimated OR for developing PD in individuals carrying 3 variants was 5.89. We demonstrated for the first time that SNPs in SNCA, LRRK2 and GAK interacted with each other to confer an increased risk of PD. In addition, PD risk increased cumulatively with the increasing number of variants.
帕金森病（PD）是一种复杂疾病，可能由基因-基因和基因-环境相互作用导致。关于PD中基因-基因相互作用的研究有限。我们和其他人之前已经表明，突触核蛋白基因（SNCA）rs356219、富亮氨酸重复激酶2（LRRK2，rs2046932和rs7304279）以及GAK激酶（rs1564282）是散发性PD的危险因素。由于SNCA的表达和α-突触核蛋白的神经毒性受LRRK2和GAK影响，我们推测它们的遗传风险变异可能会相互作用。在此，我们在中国的一个PD患者-对照队列（534例患者和435例对照）中使用多因素降维法（MDR）研究了SNCA rs356219、LRRK2 rs7304279和rs2046932以及GAK rs1564282之间的相互作用，以及SNCA、LRRK2和GAK的累积风险效应。MDR分析显示，SNCA的rs356219、LRRK2的rs2046932和GAK的rs1564282之间存在显著的基因-基因相互作用。此外，与那些不携带任何变异的个体相比，携带变异数量增加的个体患PD的可能性增加。携带3个变异的个体患PD的估计比值比（OR）为5.89。我们首次证明，SNCA、LRRK2和GAK中的单核苷酸多态性（SNP）相互作用会增加患PD的风险。此外，PD风险随着变异数量的增加而累积增加。
