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

描述（由申请人提供）：每年，数以百万计的美国人患上疼痛性颞下颌疾病（TMD），其中多达三分之一的人的症状变为慢性。然而，人们对慢性TMD的病因知之甚少；相反，慢性TMD的最佳预测指标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，以调查先前的风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，我们计划在多位点OPPERA前瞻性队列研究（口腔面部疼痛、前瞻性评估和风险评估；NIH/NIDCR U01-DE017018）的三个附加研究中使用现有数据。OPPERA招募了3263名年龄在18-44岁之间的人，他们在基线时接受了检查，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（即疼痛敏感性和自主神经功能），并提供了血液样本，从中提取DNA进行基因分型。在平均3年的随访期间，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。本提案将分析三个附加数据集。1)在季度健康更新问卷中增加了感知压力量表，为保留在队列中的2,743人提供了31,127个重复的心理压力测量。2) 258例TMD首次诊断时重复基线表型测量。6个月后，同样的测量再次重复，85人被诊断为慢性TMD（即持续时间6个月）。3)对于每个病例，选择匹配的对照，并收集匹配病例确诊时和6个月后的等效数据。生命过程流行病学方法将用于分析这些感知压力和疼痛调节的重复测量如何在人们的遗传易感性背景下展开，重点关注编码酶的基因，神经递质和调节疼痛感知的肾上腺素能系统受体。重复测量和潜在增长曲线方法的混合模型将评估这些危险因素可能对慢性TMD风险产生联合影响的两种定性不同途径：a)独立风险途径，其中危险因素发挥独立的加性作用；B)一个积累途径，在这个途径中，基因引起一系列因素，包括心理压力、疼痛敏感性和自主神经功能的改变。为了防止I型错误，一系列的分析将限制基因x表型相互作用的测试。根据我们的初步分析，该策略为检测表型的主要效应提供了良好的功率（>0.99），并为检测基因x病例状态相互作用（0.84）和基因x累积胁迫相互作用（0.64）提供了足够的功率。

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).