Statins, statin-related gene, and Parkinson's disease risk

描述（由申请人提供）：帕金森病（PD）是美国第二常见的神经退行性疾病，影响超过100万美国人；由于人口老龄化，这一数字正在增长。大多数患者最终发展成严重的残疾，这明显影响了他们的生活质量和他们的照顾者。因此，迫切需要开发疾病修饰或神经保护治疗方法。在我们之前的研究中，我们发现经常使用他汀类药物的人患帕金森病的风险较低。然而，我们先前分析的一个主要限制是我们没有特定他汀类药物使用的信息，这些信息是从2004年开始在我们的队列中收集的。由于他汀类药物通过血脑屏障的能力不同，因此研究他汀类药物与帕金森病风险的特定关联是很重要的。

DESCRIPTION (provided by applicant): Parkinson disease (PD) is the second most common neurodegenerative disease in the United States (US) and affects over one million Americans; this number is growing due to population aging. Most patients eventually develop severe disability, which markedly affects their quality of life and that of their caregivers. There is thu a compelling need to develop disease modifying or neuroprotective treatments. In our previous study, we found that PD risk is lower among individuals who regularly use statins. However a major limitation of our previous analyses is that we did not have information on use of specific statins, which was collected in our cohorts only starting in 2004. As statins differ in their abiliy to cross the blood brain barrier, it is important to examine their specific associations with PD risk. Further, previous studies have shown that there is considerable interindividual variation in statin responsiveness, which is strongly influenced by genetic variations. However there are no studies to examine the role of these statin-related genetic factors in PD risk to date. We therefore propose to expand our previous study to examine the potential effects of specific statins on PD risk among ~170,000 active participants in the Nurses' Health Study (NHS), and Health Professionals Follow-up Study (HPFS) during 10 years of follow-up (2004-2014). We expect to confirm 765 new incident cases of PD (283 Men and 482 women). We will further examine whether protective effects of statins remain among those with one or more PD pre-motor symptoms at the baseline. This analysis will provide the first evidence regarding whether statins could slow PD progression from pre-clinical to clinical stage. It is worth noting that the observed association between statins and PD could be confounded by indication, which is key to understanding of the therapeutic potential of statins in PD treatment. To answer this extremely important but unsolved question, we will also examine the interaction between use of statins and genes associated with statin responsiveness, in relation to PD risk. To test this gene-statin interaction, we will employ a novel method, the gene-environment set association test, in which all SNPs will be grouped together into a SNP-set using the kernel machine approach and thus the joint effect of these SNPs will be tested. This approach utilizes genetic information from all SNPs in a SNP-set simultaneously, leading to a more powerful test with reduced degrees of freedom. In contrast to methods that create a single genetic score from a set of proposed risk alleles, a benefit of the GESAT approach is that it does not require a priori knowledge of directionality for the variants. A better understanding of the potential role of statins, and statin-related genes, in PD risk will undoubtedly shed some light on the PD etiology and development of personalized prevention and early treatment strategies.