Insights into Sickle Cell Trait and Sickle Cell Disease

目的：对镰状细胞性状(SCT)的临床并发症进行系统评价 目标1：专家工作组对1970年1月至2018年6月30日发表的报道SCT与感兴趣的临床结果之间的关联的原始研究文章进行了系统审查。我们遵循系统评价的标准程序，并根据系统评价的首选报告项目(PRISMA)指南报告结果。这项研究排除了：1)非英语语言的研究文章；2)仅报道镰状细胞疾病患者、体外细胞或非人类动物的研究文章；3)仅检查生理机制、实验室参数或没有关于临床结果的信息的研究文章；4)流行率研究、病例报告、病例系列、会议摘要、社论和评论；以及5)系统综述和综述文章，在对其参考书目进行审查后，查找以前未确认的文章。)在7083项筛选研究中，41项符合纳入标准。 有强有力的证据表明，SCT与肺栓塞、蛋白尿和慢性肾脏疾病的风险呈正相关。有较强的证据表明SCT与劳力性横纹肌溶解呈正相关，而SCT与深静脉血栓形成、心力衰竭/心肌病、中风和儿童身高/体重无关联。血栓栓塞症和横纹肌溶解并发症的绝对风险很小。关于这些研究中报告的其余15项临床结果的相关性，要么数据不足，要么证据不足。请参见NAIK RP。等人，与镰刀细胞特性相关的临床结果，《内科医学年鉴》。169,619(2018)。 目标：探索基因组和环境因素对镰状细胞病和腿部溃疡的影响 目的2：镰状细胞病中腿部溃疡的研究正在进行中。截至2019年9月1日，我们已经招募了235名参与者。我们已经将皮肤微生物组研究的应计目标增加到250名参与者。我们将招募和抽样有活动溃疡的参与者，目前腿部溃疡已痊愈的参与者，以及那些以前没有腿部溃疡病史的参与者。此外，我们将比较以前发表的糖尿病足部溃疡和SCD腿部溃疡的微生物组数据集，以确定存在于不同溃疡中的微生物群落中的微生物特征(相似或不同)，这可能在愈合过程中至关重要。 目的3：我们将进行一项横断面研究，调查每个参与者的恢复力、压力、社会功能、健康行为和生活质量指标，以确定可能影响镰状细胞疾病和腿部溃疡的形成和愈合的环境因素(即社会、身体和心理社会)。 目的4：我们将进行基因组测序，以寻求确定遗传修饰物在有或没有腿部溃疡的患者中的作用。具体地说，我们将在参与者中进行全基因组测序，以研究导致患者群体腿部溃疡变异的遗传因素。 目标5：我们将为洞察力研究参与者开发和评估基因组结果返回计划。我们将进行一项人种学研究，以收集纵向数据，以检查接受基因组学结果的研究参与者，并评估随着时间的推移的健康行为和治疗决定。我们预测，在解决意想不到的基因组结果方面，最需要支持的研究参与者将是低收入和保险不足的个人。

GOAL: SYSTEMATIC REVIEW OF CLINICAL COMPLICATIONS OF SICKLE CELL TRAIT (SCT) For Aim 1: A systematic review of published original research articles between January 1970 and June 30, 2018 that reported an association between SCT and clinical outcomes of interest were reviewed by an expert working group. We followed standard procedures for systematic reviews and reported results according to Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. The study excluded: 1) non-English language research articles; 2) research articles that reported exclusively on patients with sickle cell disease, in vitro cells, or nonhuman animals; 3) research articles that solely examined physiological mechanisms, laboratory parameters, or had no information on clinical outcomes; 4) prevalence studies, case reports, case series, meeting abstracts, editorials and commentaries; and 5) systematic reviews and review articles after their bibliographies had been reviewed for previously unidentified articles.) Of 7,083 screened studies, 41 met inclusion criteria. There was strong evidence for a positive association between SCT and risk for pulmonary embolism, proteinuria, and chronic kidney disease. There was moderately strong evidence for a positive association between SCT and exertional rhabdomyolysis and for a null association between SCT and deep venous thrombosis, heart failure/cardiomyopathy, stroke, and pediatric height/weight. Absolute risks for the thromboembolism and rhabdomyolysis complications were small. There were either insufficient data or low strength of evidence regarding associations for the remaining 15 clinical outcomes reported in these studies. See Naik RP. et al., Clinical Outcomes Associated With Sickle Cell Trait, Annals of Internal Medicine. 169, 619 (2018). GOAL: EXPLORING THE GENOMIC AND ENVIRONMENTAL CONTRIBUTIONS TO SICKLE CELL DISEASE AND LEG ULCERS Aim 2: The study of leg ulcers in sickle cell disease is ongoing. As of September 1, 2019, we have recruited 235 participants. We have increased our accrual goal for the skin microbiome study up to 250 participants. We will recruit and sample participants with active ulcers, currently with a healed leg ulcer, and those with no previous history of leg ulcers. Additionally, we will compare a previously published microbiome dataset from diabetic foot ulcers to SCD leg ulcers to identify microbial signatures (similarities or differences) that exist in the microbial communities present in the different ulcers, which may be important in the healing process. Aim 3: We will conduct a cross-sectional study to investigate, resilience, stress, social function, health behaviors, and quality of life indicators for each participant with the goal of identifying environmental (i.e. social, physical, and psychosocial) factors that may impact sickle cell disease and the formation and healing of leg ulcers. Aim 4: We will conduct genomic sequencing to seek to identify the role of genetic modifiers in patients with and without leg ulcers. Specifically, we will conduct whole genome sequencing in the participants to study the genetic factors responsible for variation in leg ulceration in our patient population. Aim 5: We will develop and evaluate a return of genomic results program for INSIGHTS study participants. We will conduct an ethnographic study to collect longitudinal data to examine study participants that receive genomics results and assess health behaviors and treatment decisions over time. We predict that the population of study participants that are most in need of support in addressing unexpected genomic results will be low-income and under-insured individuals.