Contributions of biopsychosocial factors in sickle cell disease pain

摘要 在SCD患者中，疼痛会导致负面的身体和情绪后果。一 充分解决SCD疼痛的一个重要障碍是关于基础疾病的信息不足。 影响患者所经历的不同程度和类型的疼痛的机制。多种生物学和 心理因素（即，环境压力）到目前为止已知的有助于其他疼痛条件下- 在SCD学习。精氨酸加压素受体1A是一种7跨膜结构域的G蛋白多肽 与压力和疼痛有关的神经系统。受体基因启动子（AVPR 1A）中的rs 10877969 SNP是 与急性疼痛和压力相关疼痛和加压素系统相关的方面需要进一步研究。 研究SCD中疼痛的潜在贡献。我将利用现有的数据对几种加压素- 相关的生物/心理社会因素和定量感觉测试（QST）来研究这些机制 (and潜在的相互作用）。我还将招募一个新的成人SCD研究队列， 次要的探索性目标是对SCD疼痛相关遗传因素进行无偏倚的全基因组搜索， 修饰语在我们大量的特征鲜明的主题中。我提出三个具体目标：目标1。担任设定 从172名患有SCD的非洲裔美国人的数据集，我将进行统计分析：（a）为了测试 AVPR 1A基因型（rs 10877969）和SCD实验疼痛值（QST热和机械疼痛）之间 疼痛阈值），其将确定疼痛阈值是否基于AVPR 1A基因型而变化（即，的基因 X环境交互作用）。假设：热和机械疼痛阈值将因基因型而异（ 基因型将预测QST疼痛阈值）。(b)为了检验SCD临床疼痛是否与 (API平均疼痛强度（0-10级）和环境压力（PSQ;感知压力 问卷）受到rs 10877969基因型的调节。假设：基因型会影响相关性 环境压力和临床疼痛之间的联系目标二。这项工作还将涉及招募和定性 一个新的50名成人SCD患者的队列，研究加压素系统的其他生物效应物， 机制洞察：（a）测试疼痛和应激表型（包括QST、API和PSQ）的关系 AVPR 1A基因表达（通过定量RT-PCR测量白细胞AVPR 1A mRNA水平）和 启动子甲基化(b)探索精氨酸加压素（替代和肽素）血浆的变异性 注意力集中以及与疼痛和压力的联系。这些数据将用于计划未来的R 01研究。目标3： 作为一项试点发现研究，为了扩大对遗传性SCD疼痛调节剂的研究，我将进行全基因组研究。 基于疼痛表型（API）的联合患者集（172+50）中的相关性研究（GWAS）。目标1和 2将阐明加压素系统在SCD疼痛中的作用，并可能为未来的研究提供见解 预测和治疗这一人群的疼痛，特别是与压力有关的疼痛。探索目标3可能 确定基因和途径，以进一步研究SCD疼痛的未来研究。

Abstract In patients with SCD, pain results in an amalgam of negative physical and emotional consequences. A significant barrier to adequately address the pain of SCD is the insufficient information about underlying mechanisms affecting the variable degree and types of pain experienced by patients. Multiple biological and psychological factors (i.e., environmental stress) known so far to contribute to other pain conditions are under- studied in SCD. The arginine vasopressin receptor 1A is a 7-transmembrane domain G-protein polypeptide that is involved in stress and pain. The rs10877969 SNP in the receptor gene promoter (AVPR1A) is associated with aspects of acute pain and stress-related pain and the vasopressin system warrant further investigation into potential contributions to pain in SCD. I will utilize existing data for several vasopressin- related biological/psychosocial factors and quantitative sensory testing (QST) to investigate these mechanisms (and potential interactions) in SCD pain. I will also recruit a new study cohort of adults with SCD for a secondary, exploratory goal of performing an unbiased genome-wide search for SCD pain-related genetic modifiers in our large set of well-characterized subjects. I propose three specific aims: Aim 1. In an established data set from of 172 African Americans with SCD, I will perform statistical analysis: (a) To test for associations between AVPR1A genotype (rs10877969) and SCD experimental pain values (QST thermal and mechanical pain thresholds), which will determine whether pain thresholds vary based on AVPR1A genotype (i.e., a gene X environment interaction). Hypothesis: Thermal and mechanical pain thresholds will differ by genotype (the genotype will predict the QST pain thresholds). (b) To test whether the relationship between SCD clinical pain (API; Average Pain Intensity measured on 0-10 scale) and environmental stress (PSQ; Perceived Stress Questionnaire) is moderated by the rs10877969 genotype. Hypothesis: Genotype will influence the correlation between environmental stress and clinical pain. Aim 2. This work will also involve recruiting and characterizing a new cohort of 50 adults with SCD to study additional biological effectors of the vasopressin system for mechanistic insight: (a) To test for relationship of pain and stress phenotypes (including QST, API and PSQ) with AVPR1A gene expression (leukocyte AVPR1A mRNA levels measured by quantitative RT-PCR) and with promoter methylation. (b) To explore the variability in arginine vasopressin (surrogate copeptin) plasma concentration and associations with pain and stress. The data will be used to plan a future R01 study. Aim 3. As a pilot discovery study, to expand the search for genetic SCD pain modifiers, I will perform genome-wide association studies (GWAS) in the combined patient set (172+50) based on pain phenotype (API). Aims 1 and 2 will shed light on the role of the vasopressin system in SCD pain, and may provide insight for future studies into prediction and treatment of pain in this population, particularly stress-related. Exploratory Aim 3 may identify genes and pathways to investigate further in future studies of SCD pain.