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

遗传和社会心理对慢性 TMD 及相关疼痛的影响

• 批准号: 8713244
• 负责人: LUDA DIATCHENKO
• 金额: $ 289.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713244
• 关键词: Abdomen; Acute; Acute Pain; Address; Adult; Affect; American; Characteristics; Chronic; Clinical; Cohort Analysis; Cohort Studies; DNA; Data; Development; Disease; Enrollment; Etiology; Evaluation; Event; Exons; Fibrinogen; Functional disorder; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genital system; Genome; Genotype; Headache; Health Care Costs; Individual; Irritable Bowel Syndrome; Knowledge; Low Back Pain; Measures; Minor; National Institute of Dental and Craniofacial Research; Orofacial Pain; Pain; Participant; Patients; Persistent pain; Phase; Phenotype; Physiological; Psychosocial Influences; Public Health; Quality of life; Recording of previous events; Recruitment Activity; Relative (related person); Research Design; Resolution; Risk; Risk Assessment; Risk Factors; Sampling; Sensory; Site; Symptoms; Temporomandibular Joint Disorders; Time; United States National Institutes of Health; base; case control; chronic pain; clinically relevant; cohort; design; experience; follow-up; genetic association; genetic variant; genome wide association study; genotyping technology; member; novel; prospective; psychologic; psychological distress; public health relevance

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.

描述（由申请人提供）：虽然几乎每个人都会在某个时候经历过急性疼痛，但慢性疼痛给公众健康带来了沉重的负担，降低了数千万美国人的生活质量，并产生大量的医疗保健费用。然而，人们对导致急性疼痛转变为慢性疼痛的机制知之甚少。因此，即使最好的治疗方法效果也有限。关于病因学的一个可能线索是，患有一种慢性疼痛的患者经常会在身体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病症的发展是由特定的遗传变异和表型危险因素（即心理困扰、疼痛放大和临床疼痛特征）引起的。这一假设基于我们在多站点 OPPERA 项目（口面部疼痛、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。 2006-08 年，我们招募了 3,263 名健康成年人，其中 233 人在 3 年随访期间出现急性 TMD。急性 TMD 的危险因素与慢性 TMD 的遗传和表型危险因素明显不同。此外，86% 的慢性 TMD 病例患有四种慢性特发性疼痛中的一种或多种：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，我们提出了三个新目标，旨在揭示有关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 转变为慢性 TMD 风险的表型和基因型，我们将招募 1,000 名患有急性 TMD 的新队列，对他们进行为期 6 个月的跟踪，以识别预计有 400 名进展为慢性 TMD 的人。目标 2 将确定五种以下一种或多种的危险因素：特发性疼痛 (IPC)：TMD、HA、LBP、IBS 和/或 WBP。后续评估将在 OPPERA-I 前瞻性队列研究的参与者中进行，预计将有 640 名 IPC 患者。基线测量的现有表型和基因型将用于预测相对于对照的 1 个 IPC 与 2 个 IPC 的风险。目标 3 将识别与慢性 TMD 相关的遗传变异。一项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。复制将使用一个由 n=1,000 名慢性 TMD 病例和 n=1,000 名对照组成的新队列。这些发现将与目标 1 队列的 GWAS 分析进行对比，以确定对急性和慢性 TMD 有不同贡献的基因。根据这些发现和其他研究中经过验证的关联，将选择 12 个基因进行罕见遗传变异的外显子测序。这些拟议研究产生的知识将对多种重叠的排病风险因素的科学理解产生重大影响。此外，研究结果将为临床医生及其患者带来直接好处， 阐明 TMD 患者慢性和特发性疼痛的机制。