Insights into Sickle Cell Trait and Sickle Cell Disease

National Human Genome Research Institute

Investigators

Linked publications & trials

Abstract

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). Aim 2: Conduct a cross-sectional study using the data from the All of Us program to identify the difference in frequency of reported SCT-related clinical outcomes between known SCT-carriers and a randomized matched sample of individuals without known history of SCT. This analysis will utilize electronic health records and self-reported data from the All of Us database. Further genomic analysis of the All of Us cohort will be conducted in phase two of this project. GOAL: EXPLORING THE GENOMIC AND ENVIRONMENTAL CONTRIBUTIONS TO SICKLE CELL DISEASE AND LEG ULCERS Aim 3: The study of leg ulcers in sickle cell disease is ongoing. As of August 23, 2021, we have recruited 276 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. An initial analysis of 42 ulcers from our cohort was published in May 2021, which showed a predominance of anaerobic bacteria and opportunistic pathogens including Staphylococcus, Corynebacterium, and Finegoldia. Aim 4: 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. Recently, we looked at hair cortisol content (HCC) in 73 study participants who willingly provided a hair sample with the objective to determine the relationship between this stress biomarker and other clinical indicators of sickle cell disease. We found that HCC was lower among individuals who had greater than 30% hemoglobin S, compared with those who had less than 30% hemoglobin S (W=272.5, P=0.01). Lower HCC was also associated with report of not being on a chronic transfusion program (=48.34, SE=14.09, P=0.001) and higher ferritin levels (=-0.006, SE=0.002, P=0.02). Furthermore, HCC was significantly correlated with serum cortisol (rs=0.26, P=0.03) and corticosterone (rs=0.29, P=0.01). Aim 5: 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 6: We will conduct qualitative study of 30 individuals living with sickle cell disease regarding their attitudes and opinions regarding return of secondary results. We will also conduct case study to examine study participants that receive secondary genomic results and assess health behaviors and treatment decisions over time. GOAL: EXAMINE COVID-19 PANDEMIC IMPACTS INDIVIDUALS LIVING with SICKLE CELL DISEASE Aim 7 and 8: We will survey and conduct interviews to understand how the COVID-19 pandemic impacts individuals living with SCD, with a focus on the major physical and psychosocial facets of their disease referenced above including the presentation of pain, health care utilization, and social and behavioral health. We are particularly interested in how disease severity, pain frequency and severity, frequency and quality of healthcare services, emotional distress, sleep disturbance, perceived stress, and resilience affect the overall psychosocial well-being of individuals living with SCD during this current pandemic. As of July 2022, we have completed all waves of data collection. We examined longitudinal reslience in 97 adults living with SCD, comparing pre and during COVID pandemic resilience levels. Results showed that the psychological resilience of our study cohort had significantly decreased (0.19, p=0.01) over time. Resilience during the pandemic was associated with better mental health and physical health and lower perceived stress and emotional distress. In addition, results showed that marital status, education level, and employment were significantly associated with the psychological resilience