Sitosterolemia Spectrum in Qatari Population

This project investigates sitosterolemia, a rare inherited disorder characterized by the accumulation of plant-based sterols in the body's tissues. The disorder is caused by mutations in the ABCG5 and ABCG8 genes responsible for the transport of plant sterol (xenosterols) out of the body, leading to an increased risk of premature cardiovascular disease. The study aims to find the correlation between high levels of sitosterol in the blood and mutations in the ABCG5/8 genes or related genes. The study used a whole-genome sequencing dataset of 6,218 adult individuals from the Qatar Genome Program along their clinical and laboratory results from the Qatar Biobank database. We used a candidate-gene screening approach and a genome-wide association study to map known and novel loci to the phenotype and establish allele frequencies. The investigation identified several variants that possess potential implications for sitosterolemia, including a novel pathogenic/ likely pathogenic mutation in two different cohorts in the Middle East (Qatar and Lebanon). The study also detected seven independent Genome-Wide Association Studies (GWAS) variants associated with sitosterolemia in the Qatari population and confirmed the two previously reported variants. We further conducted a meta-analysis using the largest cohort of European-ancestry and we replicated most of the reported variants while providing significant support for the association of variants in SCARB1 & ABO with sitosterolemia. Finally, the study devised the first Polygenic Risk Score for Sitosterolemia to gauge the polygenic contribution to sitosterolemia and our results ascertained the highest reliability of the tool. In conclusion, this is the first study that sheds light on sitosterolemia in the Middle East region using GWAS and its findings will impact personalized treatment of hypercholesterolemia in general while showing the importance of building up population specific multi-omics databases.