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

描述（由申请人提供）：虽然几乎每个人都在某个时候经历过急性疼痛，但慢性疼痛对公共卫生造成了深刻的负担，降低了数千万美国人的生活质量，并产生了大量的医疗费用。然而，关于导致从急性疼痛到慢性疼痛转变的机制知之甚少；因此，即使最好的治疗方法效果也有限。关于病因的一个可能线索是，患有一种形式的慢性疼痛的患者通常会在身体的其他部位经历慢性疼痛。在这个项目中，我们假设从急性疼痛到慢性疼痛的转变以及多种慢性疼痛状况的发展是由特定的遗传变异和表型危险因素(如：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位点OPPERA项目（口腔面部疼痛、前瞻性评估和风险评估；NIH/NIDCR U01-DE017018）中对颞下颌疾病（TMD）的研究。2006- 2008年，我们招募了3263名健康成人，其中233人在3年随访期间患上了急性TMD。急性TMD的危险因素与慢性TMD的遗传和表型危险因素有显著差异。此外，86%的慢性TMD病例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）或广泛的身体疼痛（WBP）。在这个竞争性更新应用中，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向慢性TMD转变风险的表型和基因型，我们将招募1000名急性TMD成年患者，随访6个月，以确定400名进展为慢性TMD的患者。目标2将确定以下五种疾病中一种或多种的危险因素：特发性疼痛状况（IPCs）： TMD、HA、LBP、IBS和/或WBP。将对opopera - i前瞻性队列研究中的患者进行随访评估，确定预计有640名IPC患者。基线时测量的现有表型和基因型将用于预测相对于对照组的1个IPC和2个IPC的风险。目的3将确定与慢性TMD相关的遗传变异。一项发现阶段的全基因组关联研究（GWAS）将使用来自1000例opopera - i慢性TMD病例和1000例opopera - i对照的现有DNA。复制将使用n= 1000例慢性TMD病例和n= 1000例对照的新队列。这些发现将与Aim 1队列的GWAS分析进行对比，以确定导致急性和慢性TMD差异的基因。基于这些发现和其他研究证实的关联，将选择12个基因进行罕见遗传变异的外显子测序。从这些拟议的研究中产生的知识将对多种重叠疾病的风险因素的科学理解产生重大影响。此外，这些发现将对临床医生和他们的病人直接有益，

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.