Genetic Architecture And Clinical Outcomes Of The Fredrickson-Levy-Lees Dyslipoproteinemias

Background and Aims The genetic basis and clinical relevance of the classical Fredrickson-Levy-Lees (FLL) dyslipoproteinemia classifications has not been studied in general population-based cohorts. We aimed to evaluate the phenotypic and genetic characteristics of FLL disorders. Methods Among UK Biobank participants free of prevalent coronary artery disease (CAD), we used blood lipids and apolipoprotein B concentrations to infer FLL classes (Types I, IIa, IIb, III, IV, and V). For each FLL class, Cox proportional hazards regression estimated risk of incident CAD. Phenome-wide association testing was performed. GWAS were performed, followed by in silico causal gene prioritization and heritability analyses. Prevalence of disruptive Mendelian lipid variants was assessed from whole exome sequencing. Results Of 450,636 individuals, 259,289 (57.5%) met criteria for a FLL dyslipoproteinemia: 63 (0.01%) type I; 40,005 (8.9%) type IIa; 94,785 (21.0%) type IIb; 13,998 (3.1%) type III; 110,389 (24.5%) type IV; and 49 (0.01%) type V. Over median 11.1 years follow-up, compared to normolipidemics the type IIb pattern conferred the highest hazard of incident CAD overall (HR 1.92, 95% CI 1.84-2.01, P <0.001) and in meta-analysis across matched non-HDL-C strata (HR 1.45, 95% CI 1.30-1.60). GWAS revealed 250 loci associated with FLL, of which 13 were shared across all classes; compared to GWAS of isolated lipid traits, 72 additional loci were detected. Mendelian lipid variants were rare (2%), but polygenic heritability was high, ranging from 23% (type III) to 54% (type IIb). Conclusions FLL classes have distinct genetic architectures yielding new insights for cardiometabolic disease beyond single lipid analyses. ### Competing Interest Statement Dr. Natarajan reports grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, spousal employment and equity at Vertex, consulting income from Apple, AstraZeneca, Novartis, Genentech / Roche, Blackstone Life Sciences, Foresite Labs, and TenSixteen Bio, and is a scientific advisor board member and shareholder of TenSixteen Bio and geneXwell, all unrelated to this work. The other authors report no disclosures. ### Funding Statement Dr. Gilliland is partially supported by the National Heart, Lung, and Blood Institute T32 grant 5T32HL125232. Dr. Dron is supported by the Canadian Institute of Health Research as a Banting Postdoctoral Research Fellow. Drs. Peloso and Natarajan are supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL127564). In addition, Dr. Natarajan is supported by grants from the National Heart Lung and Blood Institute (R01HL148050, R01HL151283, R01HL148565, R01HL135242, R01HL151152), National Institute of Diabetes and Digestive and Kidney Diseases (R01DK125782), Fondation Leducq (TNE-18CVD04), and Massachusetts General Hospital (Paul and Phyllis Fireman Endowed Chair in Vascular Medicine). ### 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 research was conducted under UK Biobank application number 7089. The Mass General Brigham Institutional Review Board approved secondary use of these data (2013P001840). 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data underlying this article were accessed from the UK Biobank under Application number 7089. UK Biobank individual-level data are available for request by application (www.ukbiobank.ac.uk).