Familial Combined Hypercholesterolemia, Hypercholesterolemia, Autosomal Dominant, Hypercholesterolemia, Autosomal Recessive
Conditions
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
Brief 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.
Detailed description
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.
Interventions
GENETICWhole Genome Sequencing
Participants in this arm will have their blood sample analyzed by whole-genome sequencing (WGS) and will be given access to Predictiv™ Deoxyribonucleic acid (DNA)-based digital twin platform, a web-based interactive application with WGS results. The platform will include positive monogenic and polygenic Familial Hypercholesterolemia results and pharmacogenomics results on statins and clopidogrel. A report of positive monogenic variants will be included in their medical record. This may also include genes on the American College of Medical Genetics and Genomics (ACMG) secondary findings (SF) version 3.2 list if the participant consents to receive these incidental findings. The report will only include pathogenic, likely pathogenic, and variant of uncertain significance (VUS) results.
Sponsors
Predictiv Care, Inc.
Abu Dhabi Health Services Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Investigative site personnel will obtain the subject's identification number and study treatment assignment from the randomizer. Participants and all personnel directly involved in the study conduct will be blinded to the arm assignment until 2-3 months after enrollment when the whole-genome sequencing (WGS) report is generated.
Intervention model description
A randomized controlled clinical trial of whole-genome sequencing.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Diagnostic capabilities | From consent date until first documented report, up to 6 months | Diagnostic yield of standard-of-care (based on medical and family history) versus whole genome sequencing (WGS) for identifying monogenic and polygenic familial hypercholesterolemia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Resources Implementation for WGS in a clinical setting | Baseline to End of Study, up to 12 months | Assessed by documenting resources necessary for each phase, including execution of WGS, reporting of results, and overall evaluation, |
| Participant characteristics | Baseline | Age, sociodemographic, personal and family history |
| Prognostic capabilities of standard-of-care | Baseline to End of Study, up to 12 months | Prognostic capabilities of standard-of-care (based on medical and family history) versus whole genome sequencing for predicting outcomes and management in monogenic and polygenic familial hypercholesterolemia. |
| Changes in Health Care Utilization | Baseline to End of Study, up to 12 months | Assessed by reviewing medical records comparing number of services and procedures received related to the diagnosis. |
| Clinician Attitudes About WGS | Baseline | A self-built survey was created to assess physicians' perspective and attitude toward WGS |
| Change in Perceived Utility | Baseline, post-disclosure of results (approximately 2-3 months after enrollment), 6 months post-enrollment | Assessed using novel participant surveys via questions including: attitudes towards DNA testing and results, understanding of results, change in expectations, confidence, concerns. |
Countries
United Arab Emirates
Contacts
Primary ContactAlina Naeem, MBBS
Backup ContactMhy-Lanie Adduru, MD
Outcome results
None listed