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Abstract Introduction: Heterozygous inheritance of hemoglobin S (HbAS) is known as sickle cell trait (SCT). While most individuals with SCT do not experience clinical effects, studies have shown that a subset of individuals with SCT may develop chronic complications such as renal disease and venous thromboembolism or rare, acute complications such as splenic infarction and exertional rhabdomyolysis. The objective of the Achieving Understanding of the Natural history of sickle cell Trait (AUNT) study is to define the variability in SCT phenotype(s) through an assessment of clinical and laboratory findings to better understand red blood cells (RBC) characteristics and identify the subset of people with SCT who may be at risk of clinical sequelae. Here we report an interim analysis on 164 individuals. Methods: AUNT is an ongoing cross-sectional, multi-center, prospective study with a target enrollment of N=700 individuals with SCT. Participants are recruited from 12 member centers of the National Alliance of Sickle Cell Centers (NASCC) across the United States. Inclusion criteria are a confirmed diagnosis of SCT and >/=18 years of age. Those with a history of stem cell transplants or end-stage renal disease are excluded. All participants complete clinical and demographic surveys, a validated pain instrument, and provide samples. Laboratories include: a CBC, reticulocyte count, haptoglobin, D-dimer, CMP, urinalysis, and urine albumin/Cr assessments. Other investigations include RBC enzyme analyses, α-globin gene evaluation, and high-performance lipid chromatography (HPLC). Oxygenscan Laser Optical Rotational Red Cell Analyzer (Lorrca) (RR Mechatronics, The Netherlands) is performed to assess RBC deformability. The Lorrca measures RBC rheology, including the Elongation Indexes (EI) and Point of Sickling (PoS), which identifies the specific oxygen tension at which RBCs sickle. The in vitro Lorrca environment can be manipulated to increase RBC stress (denoted here as modified Lorrca). Results: In this interim analysis, we found that the modified Lorrca in vitro assay was more sensitive to changes in RBC deformability under hypoxia in SCT than the standard Lorrca. Specifically, we identified that 5% (8/164) of individuals with SCT in the cohort have RBCs that sickle in the standard Lorrca compared to 25% (41/164) when under a stressed in vitro environment using the modified Lorrca, which is performed at slightly acidic pH to more closely mimic physiologic capillary conditions. One-third (33%) of SCT individuals co-inherited α-globin gene abnormalities, which is consistent with prior studies. The α-globin gene abnormalities partly explained differences in in-vitro sickling in both the standard and modified Lorrca. Additionally, co-inheritance of α-globin gene deletions was associated with lower %HbS (%HbS range 25.2% to 36.4%), lower hemoglobin, and decreased markers of hemolysis. In this interim study, individuals without α-globin gene deletions and those with complex α-globin gene inheritance (additions) reported more self-history of ophthalmologic problems than those with α-globin deletions. Conclusions: This is the first study of individuals with SCT designed to prospectively examine the clinical and laboratory phenotype and to assess the impact of other RBC abnormalities. Despite previous reports of clinical complications in individuals with SCT, it is not clear which individuals could manifest these issues or under what conditions. The early findings here suggest that there is variability in RBC phenotype in SCT and that co-inheritance of SCT with specific α-gene abnormalities may predict potential patterns of clinical and hematologic expression. These data have potentially far-reaching implications for both understanding which people with SCT may have complications and for predicting outcomes in genetic therapies for people with SCD. Identifying factors that alter the SCT or SCD physiology will inform the prevention of complications in the very rare at-risk subset of SCT people and allow for enhanced precision medicine for people with SCD.