The Omic Modifiers of Morbidity and Mortality in Sickle Cell Disease

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2023

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Abstract

Sickle cell disease (SCD) is a human genetic disorder caused by a mutation in the hemoglobin beta gene, causing sickling of red blood cells (RBCs) under hypoxic conditions, vaso-occlusion and adherence to other cells and endothelium, and downstream cellular and organ damage, ultimately resulting in higher morbidity and mortality relative to healthy people. While SCD is a Mendelian disorder defined by mutation in a single gene, the clinical presentation of people with SCD is highly heterogeneous. Typical SCD complications like acute chest syndrome (ACS), pain crises, and strokes are common but not universal, the range of severity of these outcomes is highly variable (higher morbidity, but not in all people with SCD), and life expectancy is lower on average (United States: 54 years). While the hemoglobin beta locus has been comprehensively studied as the origin of SCD, study on the other genetic and “-omic” factors that modify the disease presentation are less understood. Investigation into these omic modifiers of SCD may provide insight into many potential therapeutic targets that can greatly increase the quality of life and lifespan of people with SCD.

To advance knowledge of omic modifiers of SCD, multiple approaches combining large-scale biological datasets with new methodologies and toolkits have been used to assess SCD progression across multiple facets. Whereas prior research on SCD modifiers has been performed on smaller datasets with limited genomic data, we have performed genome-wide analyses with whole-genome sequences across much larger cohorts of people with SCD. In addition, other omic datasets are addressed. Variability in methylation at CpG sites are utilized to provide measurements of biological aging in SCD that differs from normal, healthy biological aging.

Across these analyses, a more comprehensive assessment of the omic modifiers of morbidity and mortality in SCD is achieved. Further work will serve to validate the results of these analyses and recommend omic variants for investigation in therapeutic interventions.

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Lê, Brandon Minh (2023). The Omic Modifiers of Morbidity and Mortality in Sickle Cell Disease. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/30348.

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