Genetic and Psychosocial Influences on Transition to Chronic TMD and Related Pain

描述(申请人提供)：虽然几乎每个人都会在某些时候经历急性疼痛，但慢性疼痛给公共健康带来了沉重的负担，降低了数千万美国人的生活质量，并招致了巨额的医疗费用。然而，人们对导致从急性疼痛向慢性疼痛过渡的机制知之甚少；随后，即使是最好的治疗方法，其疗效也有限。关于病因学的一个可能的线索是，患有一种形式的慢性疼痛的患者通常会经历身体其他部位的慢性疼痛。在这个项目中，我们假设从急性疼痛到慢性疼痛的转变和多种慢性疼痛状况的发展，是由特定的遗传变异和表型风险因素(即。心理困扰、疼痛放大和临床疼痛特征)。这一假设是基于我们在多地点OPPERA项目(口腔面部疼痛、前瞻性评估和风险评估；NIH/NIDCRU01-DE017018)中对颞下颌关节紊乱症(TMD)的研究。在2006-08年度，我们招募了3263名健康成年人，其中233人在3年的随访期内发生了急性TMD。急性TMD的危险因素明显不同于慢性TMD的遗传和表型危险因素。此外，86%的慢性TMD患者有四种慢性特发性疼痛症状中的一种或多种：头痛(HA)、腰痛(LBP)、肠易激综合征(IBS)或广泛性躯体疼痛(WBP)。在这个竞争性的更新应用中，我们提出了三个新的目标，旨在揭示关于慢性疼痛的病因和病理生理学的新信息。目的1：为了确定预测从急性TMD转变为慢性TMD风险的表型和基因类型，我们将招募1000名急性TMD成人作为新的队列，对他们进行6个月的追踪，以确定预计有400人进展为慢性TMD。目标2将确定以下五项中的一项或多项的危险因素：特发性疼痛状况(IPC)：TMD、HA、LBP、IBS和/或WBP。将在OPPERA-I前瞻性队列研究的人群中进行后续评估，确定预计有640人患有1例IPC。在基线上测量的现有表型和基因类型将被用来预测相对于对照的1个IPC和2个IPC的风险。AIM 3将识别与慢性TMD相关的基因变异。一项发现阶段的全基因组关联研究将使用1,000例OPPERA-I慢性TMD病例和1,000例OPPERA-I对照的现有DNA。复制将使用n=1,000例慢性TMD病例和n=1,000名对照的新队列。这些发现将与GWAS对AIM 1的队列分析进行对比，以确定对急性和慢性TMD有不同贡献的基因。基于这些发现和来自其他研究的验证关联，将选择12个基因用于稀有遗传变异的外显子测序。这些拟议研究产生的知识将对科学理解多种重叠的PAI情况的风险因素产生重大影响。此外，这些发现将对临床医生和他们的患者有直接的好处， 阐明TMD患者慢性和特发性疼痛的潜在机制。

DESCRIPTION (provided by applicant): While virtually everyone experiences acute pain at some time, it is chronic pain that exacts a profound burden on the public health, reducing quality of life for tens of millions Americans, and incurring substantial health care costs. Yet little is known about mechanisms that cause a transition from acute to chronic pain; subsequently, event the best of treatments have limited efficacy. One likely clue regarding etiology is that patients who have one form of chronic pain often experience chronic pain elsewhere in the body. In this project, we hypothesize that the transition from acute to chronic pain and the development of multiple chronic pain conditions, are caused by specific constellations of genetic variants and phenotypic risk factors (ie. psychological distress, pain amplification and clinical pain characteristics). This hypothesis is based on our studies of temporomandibular disorder (TMD) in the multi-site OPPERA project (Orofacial Pain, Prospective Evaluation and Risk Assessment; NIH/NIDCR U01-DE017018). In 2006-08, we enrolled 3,263 healthy adults, 233 of whom developed acute TMD during the 3-year follow-up period. Risk factors for acute TMD differed conspicuously from genetic and phenotypic risk factors for chronic TMD. Furthermore, 86% of chronic TMD cases had one or more of four chronic, idiopathic pain conditions: headache (HA), low back pain (LBP), irritable bowel syndrome (IBS) or widespread bodily pain (WBP). In this competitive renewal application, we propose three new aims designed to reveal novel information regarding the etiology and pathophysiology of chronic pain. Aim 1: To identify phenotypes and genotypes that predict risk of transition from acute TMD to chronic TMD, we will enroll a new cohort of 1,000 adults who have acute TMD, following them for six months to identify an expected 400 who progress to chronic TMD. Aim 2 will identify risk factors for one or more of five: idiopathic pain conditions (IPCs): TMD, HA, LBP, IBS and/or WBP. Follow-up assessments will be conducted among people in the OPPERA-I prospective cohort study, identifying an expected 640 people who have ¿1 IPC. Existing phenotypes and genotypes measured at baseline will be used to predict risk of 1 IPC vs. ¿2 IPCs relative to controls. Aim 3 will identify genetic variants associated with chronic TMD. A discovery-phase genome wide association study (GWAS) will use existing DNA from 1,000 OPPERA-I chronic TMD cases and 1,000 OPPERA-I controls. Replication will use a new cohort of n=1,000 chronic TMD cases and n=1,000 controls. Those findings will be contrasted with GWAS analysis of the cohort for Aim 1 to identify genes that contribute differentially to acute and chronic TMD. Based on these findings and validated associations from other studies, twelve genes will be selected for exon sequencing of rare genetic variants. Knowledge generated from these proposed studies will have a significant impact on scientific understanding of risk factors for multiple, overlapping pai conditions. Moreover, the findings will be of direct benefit for clinicians and for their patients, elucidating mechanisms underlying chronic and idiopathic pain in people with TMD.