Contributions of biopsychosocial factors in sickle cell disease pain

摘要 在SCD患者中，疼痛会导致身体和情感上的负面后果。一个 充分解决SCD的痛苦的重大障碍是关于潜在疾病的信息不足 影响患者经历的不同程度和类型的疼痛的机制。多个生物和 到目前为止已知的导致其他疼痛情况的心理因素(即环境压力)- 曾在SCD学习。精氨酸加压素受体1A是一种7-跨膜区G蛋白多肽 这与压力和疼痛有关。受体基因启动子(AVPR1A)中的rs10877969 SNP为 与急性疼痛和应激相关疼痛相关的方面，以及加压素系统需要进一步 对SCD患者疼痛的潜在贡献进行调查。我会利用现有的数据研究几种加压素- 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 (以及潜在的相互作用)与SCD疼痛。我还将招募一组患有SCD的成年人进行新的研究 其次，探索性目标是对SCD疼痛相关基因进行无偏见的全基因组搜索 在我们的大集合中的修饰语很好地刻画了主题。我提出了三个具体目标：目标1.在一个既定的 从172名患有SCD的非裔美国人的数据集中，我将进行统计分析：(A)测试关联性 AVPR1A型(Rs10877969)与SCD实验痛值(QST热痛值和机械痛值)之间的关系 痛阈值)，它将确定痛阈值是否基于AVPR1A型(即，基因 X环境交互作用)。假设：热痛感和机械性痛觉阈值将因基因而异( 基因将预测QST痛阈值)。(B)检验SCD与临床疼痛的关系 (API；平均疼痛强度在0-10分范围内测量)和环境压力(PSQ；感知压力 调查问卷)由rs10877969基因控制。假设：基因分型会影响相关性 在环境压力和临床疼痛之间。目标2.这项工作还将涉及招募和定性 一组新的50名成年SCD患者研究加压素系统的额外生物效应物 机械洞察力：(A)测试疼痛和应激表型的关系(包括QST、API和PSQ) 用AVPR1A基因表达(用定量RT-PCR测量白细胞AVPR1AmRNA水平)和用 启动子甲基化。(B)探讨精氨酸加压素(替代谷氨酸加压素)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R01研究。目标3. 作为一项先导性的发现研究，为了扩大对遗传SCD疼痛改良剂的搜索，我将在全基因组范围内进行 基于疼痛表型(API)的联合患者组(172+50)中的关联研究(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。 来预测和治疗这一人群中的疼痛，特别是与压力相关的疼痛。探索性目标3可能 确定基因和途径，以便在未来SCD疼痛的研究中进一步研究。

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.