Genes for human chronic pain syndromes through whole genome sequencing

通过全基因组测序发现人类慢性疼痛综合征的基因

• 批准号: 8675833
• 负责人: Kari Stefansson
• 金额: $ 52.67万
• 依托单位: DECODE GENETICS, EHF
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-26 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675833
• 关键词: Acute; Acute Pain; Alveolar; Behavioral; Bicuspid; Biological Process; Budgets; Cardiac Surgery procedures; Chronic; Craniofacial Pain; DNA Microarray Chip; Data; Databases; Development; Diabetic Neuropathies; Dimensions; Disease Association; Drops; Drug Utilization; Etiology; Family; Frequencies; Functional disorder; Gene Frequency; Genealogy; Genes; Genetic; Genome; Genomics; Genotype; Grant; Haplotypes; Heart Diseases; High Prevalence; Human; Iceland; Individual; Injury; Knowledge; Lead; Mastectomy; Mechanics; Medical; Methods; Modeling; Molecular; Neuropathy; Online Systems; Operative Surgical Procedures; Opiates; Oral Surgical Procedures; Pain; Pathway interactions; Patients; Peripheral; Persistent pain; Pharmaceutical Preparations; Phase; Phenotype; Population; Population Control; Postherpetic neuralgia; Process; Public Health; Questionnaires; Reaction; Recording of previous events; Risk; Sample Size; Somatoform Disorders; Syndrome; System; Temporomandibular Joint Disorders; Temporomandibular joint disorder pain; Thoracotomy; Tissues; Tooth Extraction; Tooth structure; Toothache; Trauma; Trigeminal Neuralgia; Variant; addiction; base; breast surgery; case control; chronic neuropathic pain; chronic pain; cohort; cost; cost effective; density; disability; gabapentin; genetic analysis; genetic association; genetic resource; genetic variant; genome sequencing; genome wide association study; high risk; malignant breast neoplasm; next generation sequencing; painful neuropathy; population based; pregabalin; programs; risk variant; somatosensory; trait

DESCRIPTION (provided by applicant): Chronic neuropathic pain syndromes including craniofacial and dental pain syndromes represent large unmet medical needs and are inadequately treated with current drugs. Conversion from acute pain to chronic neuropathic pain syndromes may result from maladaptive changes in the peripheral and central somatosensory system in reaction to the initial tissue injury that caused the acute pain. This project proposes t generate new knowledge on the basic pathophysiology chronic neuropathic pain by determining the genetic differences between patients who develop chronic neuropathic pain after initial tissue injury versus those who do not despite having the same acute tissue injury. We propose here to leverage the unique genetic resources gathered and developed at deCODE Genetics for whole genome sequence-based human pain genetics studies to uncover high risk variants of low frequency significantly associated to conversion from acute to chronic pain. In this project, we propose to extensively re-phenotype large cohorts with chronic neuropathic pain including common forms of craniofacial pain. We already have lists of Icelandic patients who have or are likely to have certain chronic neuropathic pain syndromes totaling over 12,000 patients. We will study large cohorts of phantom tooth pain (persistent dento-alveolar pain (PDAP)), temporomandibular disorder (TMD), and post-mastectomy pain syndrome. We will also screen a large cohort of Icelanders taking gabapentin or pregabalin for common chronic pain syndromes including diabetic neuropathy and post-herpetic neuralgia. The extra phenotyping will give us additional dimensions beyond the basic pain symptomology including quality and intensity on which to condition the genetic analysis. It may also make it easier to replicate our findings in outside pain cohorts that have already been well-phenotyped by our collaborators. We can generate whole genome sequences for large cohorts of pain syndromes and controls in Iceland more quickly and cost-effectively than in other populations. Although costs are dropping rapidly, it is still very expensive to fully sequence the genomes of the thousands of individuals that are required for well-powered disease association studies. We leverage our genealogy database and high density DNA chip data to propagate all genomic variation down to rare allelic frequencies of 0.05% from thousands of fully sequenced Icelanders to over one hundred thousand Icelanders. Using these full sequences and by sequencing the whole-genomes of 150 individuals from families with a high prevalence of either PDAP or TMD, we plan to perform whole-genome association studies of chronic neuropathic pain syndromes with large effective sample sizes, studies that would otherwise be prohibitively costly. We expect to find many new genetic associations that will increase our understanding of conversion from acute to chronic neuropathic pain syndromes. The primary data generated in this grant will be made widely available for others to build on.

描述（由申请人提供）：包括颅面和牙齿疼痛综合征在内的慢性神经性疼痛综合征，代表了巨大的未满足医疗需求，并且用当前药物治疗不足。从急性疼痛到慢性神经性疼痛综合征的转化可能是由于外周和中央体感系统的不良适应性变化而导致的，反应引起急性疼痛的初始组织损伤。该项目提出t通过确定初始组织损伤后出现慢性神经性疼痛的患者与那些尽管没有相同的急性组织损伤的患者，从而产生有关基本病理生理学慢性神经性疼痛的新知识。 我们在这里提出，以利用基于全基因组序列的人类疼痛遗传学研究在解码遗传学上收集和开发的独特遗传资源，以发现低频的高风险变异，与从急性转变为慢性疼痛的转换显着相关。在这个项目中，我们建议对慢性神经性疼痛（包括常见的颅面疼痛形式）进行广泛的大型同类型。我们已经有一个或可能患有某些慢性神经性疼痛综合症的冰岛患者列表，总计超过12,000名患者。我们将研究大量的幻影牙齿疼痛（持续性牙本质 - 肺泡疼痛（PDAP）），颞下颌疾病（TMD）和术后切除术后疼痛综合征。我们还将筛选一大批冰岛人服用加巴喷丁或前加巴林，以治疗常见的慢性疼痛综合征，包括糖尿病神经病和毛刺神经痛。额外的表型将为我们提供超出基本疼痛症状的其他维度，包括调节遗传分析的质量和强度。这也可能使我们更容易在我们的合作者对外界疼痛队列中复制我们的发现。 与其他人群相比，我们可以在冰岛更快，更具成本效率地为冰岛的大量疼痛综合症和对照组生成全基因组序列。尽管成本正在迅速下降，但完全测序的数千个人的基因组仍非常昂贵。我们利用我们的家谱数据库和高密度DNA芯片数据将所有基因组变异传播到罕见的等位基因频率，从成千上万的完全测序的冰岛人到十万冰岛人，为0.05％。使用这些完整的序列，并测序来自PDAP或TMD高流行率的150个个体的全基因组，我们计划对具有较大有效样本量的慢性神经性疼痛综合症进行全基因组关联研究，否则该研究将是昂贵的。我们希望找到许多新的遗传关联，这将增加我们对从急性神经性疼痛综合征的转化的理解。该赠款中生成的主要数据将被广泛用于其他人。