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

描述（由申请人提供）：虽然几乎每个人都会在某个时候经历急性疼痛，但慢性疼痛给公共卫生带来了沉重的负担，降低了数千万美国人的生活质量，并产生了巨额医疗保健费用。然而，人们对导致从急性疼痛转变为慢性疼痛的机制知之甚少;因此，最好的治疗方法的疗效有限。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在身体的其他地方经历慢性疼痛。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遗传变异和表型风险因素的特定星座引起的。心理困扰、疼痛放大和临床疼痛特征）。该假设基于我们在多部位OPPERA项目（口面疼痛、前瞻性评价和风险评估; NIH/NIDCR U 01-DE 017018）中对颞下颌关节紊乱病（TMD）的研究。在2006年至2008年，我们招募了3,263名健康成人，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）或广泛性身体疼痛（WBP）。在这个竞争性的更新申请中，我们提出了三个新的目标，旨在揭示慢性疼痛的病因学和病理生理学的新信息。目标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，我们将招募一个新的1,000名患有急性TMD的成年人队列，对他们进行为期6个月的随访，以确定预期的400名进展为慢性TMD的人。目标2将确定以下五种情况中一种或多种的风险因素：特发性疼痛状况（IPC）：TMD，HA，LBP，IBS和/或WBP。将在OPPERA-I前瞻性队列研究中对患者进行随访评估，确定预计有640人患有<$1 IPC。基线时测量的现有表型和基因型将用于预测相对于对照的1 IPC vs.<$2 IPC的风险。目标3将确定与慢性TMD相关的遗传变异。发现阶段全基因组关联研究（GWAS）将使用来自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例对照的新队列。这些发现将与目标1的队列GWAS分析进行对比，以确定对急性和慢性TMD有差异贡献的基因。基于这些发现和其他研究验证的相关性，将选择12个基因用于罕见遗传变异的外显子测序。从这些拟议的研究中获得的知识将对科学地理解多种重叠的派疾病的风险因素产生重大影响。此外，这些发现将直接有益于临床医生和他们的病人， 阐明TMD患者慢性和特发性疼痛的潜在机制。 公共卫生相关性：慢性疼痛是影响数千万美国人的重大公共卫生问题，许多最令人不安的疼痛状况的病因仍然知之甚少。该项目将对6,000名成年人进行研究，以评估他们首次出现的五种疼痛状况：颞下颌关节紊乱病，头痛，腰痛，腹部/生殖器疼痛和广泛疼痛。遗传，生理，心理和临床特征将被测量，以确定为什么疼痛变得持久，以及为什么有些人会发展出多种慢性疼痛状况。

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. PUBLIC HEALTH RELEVANCE: Chronic pain is a substantial public health problem affecting tens of millions of Americans, and the etiology of many of the most troubling pain conditions remains poorly understood. This project will study 6,000 adults to evaluate five such pain conditions when they first develop: temporomandibular disorder, headache, low back pain, abdominal/genital pain and widespread pain. Genetic, physiological, psychological and clinical characteristics will be measured to determine why pain becomes persistent, and why some people develop multiple of these chronic pain conditions.