Epigenetic Age Acceleration and Psychoneurological Symptoms in Sickle Cell Disease

项目总结 患有镰状细胞病(SCD)的人会出现有害的精神神经症状，如疼痛、 睡眠障碍、抑郁症状和认知障碍。在这些症状中，有一个值得注意的 个体间的变异性。很少有研究试图研究为什么有些人的情况会更糟 精神神经症状比其他人更多。识别生物因素，如表观遗传机制 影响SCD症状经验的变异性，有助于风险评估的发展 促进健康维护、生活质量和减少健康差距的工具和干预措施 人口。最近的证据表明，一个人的表观遗传年龄可能与 SCD患者的精神神经症状体验。表观遗传年龄是通过评估DNA甲基化来计算的 许多CpG基因座的模式，解释了细胞衰老或组织功能下降的速度。 过早的表观遗传年龄加速可能涉及许多生理过程，包括增加 炎症、氧化应激和线粒体功能障碍。与表观遗传年龄加速的关系 在其他慢性病人群中的精神神经症状体验最近 已确认身份。然而，表观遗传年龄加速是否发生以及是否与这些症状有关 SCD患者仍不清楚。这项横断面研究的具体目的是：1)描述 表观遗传老化DNA甲基化模式和确定表观遗传年龄加速的存在和2) 确定表观遗传年龄加速与心理神经症状(疼痛、睡眠)之间的关系 精神障碍、抑郁症状和认知功能)。DNA样本和病人- 杜克大学已经作为镰状细胞疾病联盟的一部分收集了报告的结果数据 本研究将使用研究登记处(n=92)。DNA甲基化数据将从提取的 血液样本的DNA并用于计算表观遗传年龄。因为不同的表观遗传时钟提供了 表观老化的不同度量和特征，表观年龄加速将使用 三个表观遗传钟(Horvath、Hannum和Levine)。我们还将检查计算是否来自 样本中的每个时钟都是相关的。存在的每个感兴趣的症状的患者报告数据 SCDIC注册表将用于确定与表观遗传年龄加速的关联 表观遗传时钟。这项“高风险、高回报”的研究可能为表观遗传衰老生物标记物提供新的视角 与SCD患者的症状发展和健康结局相关，代表不足 人口。生成的数据对于设计严谨和充足动力的R01研究是必不可少的 了解多层次因素的相互作用(例如，表观遗传年龄加速、社会决定因素等 例如歧视和种族主义)，造成了这一人群的症状负担和健康差距。

PROJECT SUMMARY Individuals with sickle cell disease (SCD) experience deleterious psychoneurological symptoms, such as pain, sleep disturbances, depressive symptoms, and cognitive impairment. Among these symptoms, there is notable interindividual variability. Few studies have sought to examine why some individuals experience worse psychoneurological symptoms than others. Identifying biological factors, such as epigenetic mechanisms that influence the variability of symptom experiences in SCD, can help inform the development of risk assessment tools and interventions that promote health maintenance, quality of life, and reduce health disparities in this population. Recent evidence has converged to suggest a person's epigenetic age may be associated with psychoneurological symptom experiences in SCD. Epigenetic age is calculated by assessing DNA methylation patterns at numerous CpG loci that account for the pace of cellular aging or declining tissue function. Premature epigenetic age acceleration putatively involves many physiologic processes, including increased inflammation, oxidative stress, and mitochondrial dysfunction. Associations with epigenetic age acceleration and psychoneurological symptom experiences in other chronic disease populations has recently been identified. However, whether epigenetic age acceleration occurs and if it is associated with these symptoms in individuals with SCD remains unknown. The specific aims of this cross-sectional study are to 1) characterize epigenetic aging DNA methylation patterns and determine presence of epigenetic age acceleration and 2) identify associations between epigenetic age acceleration and psychoneurological symptoms (pain, sleep disturbances, depressive symptoms, and cognitive function) in adults with SCD. DNA samples and patient- reported outcome data already collected at Duke University as part of the Sickle Cell Disease Consortium Research Registry (n=92) will be used in this study. DNA methylation data will be generated from the extracted DNA of blood specimens and used to calculate epigenetic age. Because different epigenetic clocks provide different measures and characteristics of epigenetic aging, epigenetic age acceleration will be calculated using three epigenetic clocks (Horvath, Hannum, and Levine). We will also examine whether the calculations from each of the clocks are correlated in the sample. Patient-reported data for each symptom of interest existing in the SCDIC Registry will be used to determine associations with epigenetic age acceleration for each of the epigenetic clocks. This “high risk, high return” study may provide novel insight into epigenetic aging biomarkers associated with symptom development and health outcomes in people with SCD, an underrepresented population. The data generated is essential for designing a rigorous and adequately powered R01 study to understand the interactions of multiple level factors (e.g., epigenetic age acceleration, social determinants such as discrimination and racism) that contribute to symptom burden and health disparities in this population.