integrating whole genome sequencing and digital twins into the management of hypercholesterolemia in emiratis

Conditions: Hypercholesterolemia, Autosomal Dominant; Hypercholesterolemia, Autosomal Recessive; Familial Combined Hypercholesterolemia

Summary: this pilot study investigates integrating whole genome sequencing and digital twin technology for managing hypercholesterolemia in abu dhabi clinics. it aims to establish protocols for larger future studies and incorporate genomic insights into routine medical care.

atherosclerotic cardiovascular disease (ascvd) is the leading cause of death in the middle east, with hypercholesterolemia being a significant contributor. genetic mechanisms of hypercholesterolemia in this region are not well understood. autosomal dominant hypercholesterolemia is a major factor, yet only \~7% of emiratis with familial hypercholesterolemia (fh) have these mutations. in 2013, talmud et al. identified common variants through genome-wide association studies (gwas) that suggest a polygenic cause for hypercholesterolemia in mutation-negative fh patients. a polygenic risk score based on 12 snps was validated in white european populations and is used in the uk's nhs diagnostic pipeline. distinguishing polygenic hypercholesterolemia from fh without genetic testing is challenging. these patients exhibit familial moderate hypercholesterolemia and early coronary heart disease, with elevated ldl-c, normal triglycerides, and no tendon xanthoma. their cardiovascular risk is similar to monogenic fh with age. statins, though commonly prescribed for ascvd prevention, can cause musculoskeletal symptoms leading to poor adherence, discontinuation, elevated cholesterol, and increased cardiovascular risk. many patients fail to achieve target ldl-c levels due to suboptimal dosing. certain gene variants increase the risk of statin side effects. this study seeks to integrate whole genome sequencing (wgs) technology in a clinical setting through an innovative digital twin platform. this platform allows clinicians to assess monogenic and polygenic risks in real-time and make informed statin prescribing and management decisions.

Eligibility criteria:
inclusion criteria: * patients with 2 or more ldl-c levels greater than 190 mg/dl or 5.0 mmol/l in the past 12 months * undiagnosed patients meeting possible, probable or definitive fh criteria according to dutch lipid clinic network (dlcn) criteria (eur heart j. 2011 jul;32(14):1769-818. doi: 10.1093/eurheartj/ehr158. epub 2011 jun 28.) * patients who have not been on anti-lipidemic medication in the past 3 months * ages 18-55 * emirati national * all patients must be fluent in english or arabic exclusion criteria: * - patients who do not meet the above criteria * patients with a previous diagnosis of fh * patients with a progressive debilitating illness * patient with untreated hypothyroidism, history of proteinuria, obstructive liver disease, chronic renal failure, human immunodeficiency virus infection, or on immunosuppressant or steroid or psychiatric medications * patients with untreated clinical anxiety or depression (as measured by a hospital anxiety and depression scale (hads) score of ≥ 16 on the depression subscale) * patients who are pregnant

Keywords: ldh familial hypercholesterolemia whole genome sequencing digital twins management of hypercholesterolemia emirati randomized controlled trial sanger sequencing predictiv care genomic medicine precision medicine pharmacogenomics