Effects of cumulative stress and change in pain regulation on risk of chronic TMD

描述(由申请者提供)：每年，数以百万计的美国人患上痛苦的颞下颌关节紊乱病(TMD)，其中多达三分之一的人症状变得慢性。然而，人们对慢性TMD的先兆知之甚少；相反，慢性TMD最好的预测因素是在病情已经发展时评估的疼痛特征。我们建议分析在TMD发病之前、期间和之后收集的数据，以调查先前的危险因素如何随着时间的推移而影响慢性TMD的风险。我们假设，反复的心理压力会引起疼痛调节系统的变化，导致遗传易感人群从急性疼痛过渡到慢性疼痛。为了响应PAR-09-182，我们计划使用多地点OPPERA前瞻性队列研究的三项附加研究中的现有数据(口腔面部疼痛、前瞻性评估和风险评估；NIH/NIDCRU01-DE017018)。OPPERA登记了3263名年龄在18-44岁之间的人，他们在基线上进行了检查，以确认没有TMD。他们还完成了问卷调查，接受了疼痛调节系统的生理测试(即疼痛敏感度和自主神经功能)，并提供了血液样本，从血液中提取DNA用于基因分型。在平均3年的随访期内，季度健康更新问卷确定了出现症状的人，其中258人被诊断为首发TMD。该提案将分析三个附加数据集合。1)感知压力量表被添加到季度健康更新问卷中，为队列中保留的2743人提供了31127次心理压力重复测量。2)在258例首次诊断为TMD的病例中，重复基线表型测量。6个月后，再次重复同样的措施，85人被诊断为慢性TMD(即持续6个月)。3)对于每个事件病例，选择一个匹配的对照，并在匹配的病例被诊断时和6个月后收集相同的数据。生命过程流行病学方法将被用来分析这些重复的感知压力和疼痛调节措施是如何在人们的遗传易感性的背景下展开的，重点是编码调节疼痛感知的肾上腺素系统的酶、神经递质和受体的基因。重复测量的混合模型和潜在生长曲线方法将评估两条定性不同的途径，这些危险因素可能通过两条途径对慢性TMD的风险产生联合影响：a)独立的风险途径，在其中风险因素发挥独立的、相加的作用；b)积累途径，在其中基因引起一系列涉及心理应激、疼痛敏感性和自主神经功能改变的因素。为了防止I型错误，一系列连续的分析将限制对基因x表型相互作用的测试。根据我们的初步分析，该策略提供了良好的能力来检测表型(&gt；0.99)的主效应，并提供了足够的能力来检测基因x病例-状态互作(0.84)和基因x累积胁迫互作(0.64)。

DESCRIPTION (provided by applicant): Each year, millions of Americans develop painful temporomandibular disorders (TMD), and symptoms become chronic for as many as one third of them. Yet, little is known about the antecedents of chronic TMD; instead, the best predictors of chronic TMD are characteristics of pain assessed when the condition has already developed. We propose to analyze data collected before, during and after onset of TMD to investigate how antecedent risk factors unfold over time to influence risk of chronic TMD. We hypothesize that repeated psychological stress elicits changes in pain regulatory systems, causing transition from acute to chronic pain in genetically-susceptible people. In response to PAR-09-182, we plan to use existing data in three add-on studies of the multi-site OPPERA prospective cohort study (Orofacial Pain, Prospective Evaluation and Risk Assessment; NIH/NIDCR U01-DE017018). OPPERA enrolled, 3,263 people aged 18-44 years who were examined at baseline to confirm absence of TMD. They also completed questionnaires, underwent physiologic testing of pain regulatory systems (i.e. pain sensitivity and autonomic function), and they provided a sample of blood from which DNA was extracted for genotyping. During the average 3-year follow-up period, quarterly health update questionnaires identified people who developed symptoms, and 258 of them were diagnosed with first-onset TMD. This proposal will analyze three add-on data-collections. 1) The Perceived Stress Scale was added to the quarterly health update questionnaire, providing 31,127 repeated measures of psychological stress among the 2,743 people retained in the cohort. 2) Baseline phenotypic measures were repeated when TMD was first diagnosed in the 258 incident cases. Six months later, the same measures again were repeated, and 85 people were diagnosed with chronic TMD (i.e. duration >6 months). 3) For each incident case, a matched control was selected, and equivalent data were collected at the time the matched case was diagnosed, and six months later. Life course epidemiologic methods will be used to analyze how these repeated measures of perceived stress and pain regulation unfold against the backdrop of people's genetic predisposition, focusing on genes encoding enzymes, neurotransmitters and receptors of the adrenergic system that regulate pain perception. Mixed models for repeated measures and latent growth curve methods will evaluate two qualitatively different pathways by which these risk factors might exert combined effects on risk of chronic TMD: a) an independent risk pathway, in which risk factors exert independent, additive effects; b) an accumulation pathway, in which genes give rise to a cluster of factors involving psychological stress, pain sensitivity and altered autonomic function. To guard against type I error, a sequential set of analyses will restrict tests for gene x phenotype interactions. Based on our preliminary analysis, this strategy provides good power to detect main effects of phenotypes (>0.99) to and sufficient power to detect gene x case-status interactions (0.84) and gene x cumulative stress interactions (0.64).