LDLR Variant Classification for Improved Cardiovascular Risk Prediction in Familial Hypercholesterolemia

Background Familial Hypercholesterolemia (FH) is a genetic disorder marked by high LDL cholesterol and an increased premature coronary artery disease (CAD) risk. Current dichotomous classification of LDL receptor gene ( LDLR ) variants may inadequately capture patient variability in LDL cholesterol levels and CAD risk. This study assessed a novel approach for assessing LDLR variant severity using variant-specific LDL cholesterol percentiles. Methods Participants of the Dutch FH cascade screening program were screened for 456 LDLR variants. Sex- and age-specific LDL cholesterol percentiles were computed for each LDLR variant carrier. These percentiles were used to calculate the mean LDL cholesterol percentile for each variant. Based on the variant-specific LDL cholesterol percentiles, carriers were grouped into the following strata: <75th, 75th-88th, 88th-92nd, 92nd-96.5th, 96.5th-98th, and ≥98th percentile. Additionally, variants were categorized into class 1 (LDLR deficient) and non-class 1 (often LDLR defective) variants. CAD risk between carriers in the different strata and non-carriers was compared using a Cox proportional hazard model. Results Out of 35,257 participants, 12,485 (36%) LDLR variant carriers were identified. Carriers had a 5-fold higher CAD risk compared with non-carriers. Hazard ratios for CAD increased gradually from 2.2 (95%CI 0.97-5.0) to 12.0 (95%CI 5.5-24.8) across the strata. A 7.3-fold and 3.9-fold increased CAD risk was observed in carriers of class 1 and non-class 1 LDLR variants, respectively. Conclusions This study presents a refined approach for classifying LDLR variants based on their impact on LDL cholesterol levels, allowing for more precise, genotype-specific CAD risk estimation in FH patients compared with traditional methods. ### Competing Interest Statement LFR is cofounder of Lipid Tools and reports speakers fee from Ultragenyx, Novartis, and Daiichi Sankyo. JJPK is part time CSO of New Amsterdam Pharma and part time CMO of Staten Biotech and a consultant to AgBio, Scribe, Cincor, CSL Behring, CiVi Biopharma, Draupnir, Esperion Therapeutics, Madrigal, Menarini, Omeicos, Silence Therapeutics, Sirnaomics, TTxD and North Sea Therapeutics. GKH reports research grants from the Netherlands Organization for Scientific Research (vidi 016.156.445), CardioVascular Research Initiative, European Union and the Klinkerpad fonds, institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; speaker's bureau and consulting fees from Amgen, Aegerion,Sanofi, and Regeneron until April 2019 (fees paid to the academic institution); and part-time employment and stock holder of at Novo Nordisk A/S, Denmark since April 2019. ESGS has received ad-board/lecturing fees, paid to the institution, from: Amgen, Sanofi, Astra-Zeneca, Esperion, Daiichi Sankyo, NovoNordisk, Ionis/Akcea, Amarin. The other authors report no disclosures. ### Clinical Trial Not applicable. ### Funding Statement No external funding was received. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Institutional Review Board of Amsterdam UMC, the Netherlands, and complied with the Declaration of Helsinki. All participants gave written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used in this study are available upon reasonable request from the corresponding author.