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Sickle cell disease (SCD) is associated with significant neurocognitive risk due to a combination of disease and environmental factors. Neurological complications, including overt stroke, silent cerebral infarctions, and chronic insufficiencies in oxygen and/or glucose delivery to the brain contribute to neurocognitive decline. Environmentally, patients with SCD experience greater rates of poverty and fewer protective socioeconomic factors when compared with the Black population in the United States. Both personalized (e.g. familial education and occupation) and community measures of socioeconomic status uniquely contribute to neurocognitive outcomes. However, no studies have examined the specific community-level factors that contribute to neurocognitive performance. The primary objective of this study was to investigate associations between familial and community-level social determinants with cognitive and academic outcomes in a large prospectively recruited sample of patients with SCD ranging from childhood to young adulthood. We included 103 patients with SCD (51% HbSS/HbSβ 0-thalassemia). The mean age of participants was 12.86 (SD=4.04) years. Familial socioeconomic status was measured using the Barratt Simplified Measure of Social Status (BSMSS), a composite of parent education and occupation status. Community-level (based on census block) socioeconomic variables included: poverty rate, unemployment rate, percentage of individuals with a bachelor's degree, and access to food nutrition services. Following informed consent, patients completed gold-standard neurocognitive measures supervised by a psychologist, assessing intellectual (Wechsler Abbreviated Scale of Intelligence - Second Edition) and academic functioning (Woodcock Johnson Tests of Achievement - Third Edition). Multivariate linear regression was used to examine associations between community and familial level socioeconomic status with cognitive/academic outcomes after adjusting for age, sickle genotype, and hydroxyurea exposure. Stepwise linear regression was used to identify the independent factors associated with cognitive/academic outcomes. The False discovery rate (FDR) developed by Benjamini and Hochberg was used to control for multiple testing and FDR-adjusted p-values (pFDR) Patients with SCD lived in communities with high rates of poverty (26.57%) and unemployment (13.58%) and low rates of college education (13.26%). In multivariate analyses adjusting for age, sickle genotype, and hydroxyurea exposure, IQ was associated with the BSMSS (estimate = 0.31, standard error [SE] = 0.10, p=0.003) at pFDR0.05). In contrast, reduced intellectual functioning was associated with increased poverty rates (Estimate=-0.29, SE=0.09, p=0.003), increased unemployment rates (estimate=-0.43, SE=0.18, p=0.018), increased access to food nutrition services (Estimate=-0.21, SE=0.09, p=0.015), and decreased percentage of individuals with a bachelor's degree (Estimate=0.33, SE=0.10, p=0.003) at pFDR Social determinants at the community-level contribute to intellectual development in patients with SCD independent of familial socioeconomic status. Surprisingly, academic performance was not associated with community-level social determinants. Evaluation of community-level social determinants may provide insights into potential targets for neurodevelopmental interventions. Figure 1 Figure 1. Disclosures Estepp: Global Blood Therapeutics: Consultancy, Research Funding. Hankins: Bluebird Bio: Consultancy; UpToDate: Consultancy; Global Blood Therapeutics: Consultancy; Vindico Medical Education: Consultancy.

Background: Fetal hemoglobin (HbF) is the most influential modifier of the clinical and hematologic phenotype of sickle cell disease (SCD) and is highly heritable. Low HbF is independently associated with increased white matter changes on brain imaging and poorer performance on neurocognitive measures (Ruffiuex, Child Neuropsychology, 2013). Our previous work has shown that 11 SNPs in three genes (BCL11A, MYB, and β-globin), contribute over 20% of the variance in HbF (Rampersaud, Kang. et al., 2020, under review). Clinically, these HbF-associated SNPs are associated with disease severity and frequency of pain events. However, the neurocognitive implications of these SNPs have yet to be explored. As part of a prospective longitudinal cohort study, the Sickle Cell Clinical Research and Intervention Program (SCCRIP), we evaluated the relationship between HbF-associated SNPs and neurocognitive functioning in SCD patients. Methods: We included 257 patients with SCD (69% HbSS/HbSβ0-thalassemia). The median age of participants was 13 years (range 4 - 25). We extracted genotypes for the 11 HbF-associated SNPs from whole genome sequencing data and analyzed them based on an additive genetic model. Following informed consent, patients completed a battery of gold-standard neurocognitive measures, supervised by a psychologist, assessing IQ, verbal and perceptual reasoning, working memory, processing speed, sustained attention, and executive functioning skills. HbF was the average value of measurements collected within 3 months of neurocognitive assessment, or the closest value. In univariate analyses, Kruskal-Wallis rank sum test was used to assess the associations of the 11 HbF-associated SNPs with neurocognitive measures. Linear regression was used to examine these associations adjusting for age, sickle genotype, hydroxyurea exposure, socioeconomic status (index of social vulnerability) and 5 principal components to adjust for population stratification. Benjamini and Hochberg false discovery rate (FDR) was used for multiple corrections and FDR adjusted p (pFDR) Results: One SNP in the β-globin gene, rs968857, was associated with performance on measures of IQ, verbal reasoning, working memory, and executive functioning by Kruskal-Wallis rank sum test (Figure 1) and by linear regression adjusting for covariates listed above at pFDR Conclusions: This is the first study to demonstrate a relationship between genetic modifiers of SCD and neurocognitive functioning. Beyond findings on neuroimaging and sociodemographic factors, there is little known about risk for neurocognitive deficits in SCD. The present results suggest an influence of SNP rs968857 on cognitive function, which was partially mediated by expression of HbF. rs968857, is one of four SNPs that defines almost all β-globin gene cluster haplotypes and influences HbF levels in SCD. How this SNP effects HbF and neurocognition is unknown and requires further investigation of its mechanism. The highly heritable nature of HbF may allow for future use of precision medicine. SCD patients could be stratified according to risk for neurocognitive deficits to utilize early intervention strategies, informed by genetic polymorphisms. Correlation with neuroimaging will help further elucidate the relationship between genetic modifiers and neurocognitive functioning. Future trials with larger samples are needed to validate our findings and investigate if the observed relationships differ by age or hydroxyurea treatment status. Disclosures Estepp: Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; Global Blood Therapeutics, Forma Therapeutics, Pfizer, Eli Lilly and Co: Research Funding; ASH, NHLBI: Research Funding. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Hankins:Novartis: Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; UptoDate: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; American Society of Pediatric Hematology/Oncology: Honoraria; LINKS Incorporate Foundation: Research Funding.