High Density Lipoprotein pathway as a therapeutic target for coronary heart disease: individual participant meta-analysis in 28,597 individuals with 4197 coronary events

Importance Cholesterol content in high-density lipoprotein particles (HDL-C) is associated inversely with coronary heart disease (CHD), but findings from Mendelian randomization studies and randomized trials of HDL-C raising drugs have questioned whether this link is causal. However, these analyses do not exclude a causal role for specific HDL sub-fractions of different density, mobility, size and composition. Objective To determine whether sub-components of the HDL pathway exhibit differing relationships with CHD risk. Design In seven longitudinal studies, we used factor analysis to reduce 21 measures of HDL particle size and lipid content to a smaller number of factors representing different components of the HDL pathway. We constructed factor scores and modelled their associations on CHD risk in adjusted Cox regression analyses. We pooled results using random-effects meta-analysis. Setting Seven population-, individual-, occupational- or community-based longitudinal studies in the UK and Finland. Participants 28,597 participants (49% female, mean age 59.6 years) contributed to the analysis. Exposures Sub-components of the HDL pathway, characterized by 21 measures of HDL size and lipid content based on nuclear magnetic resonance spectroscopy. Main Outcomes Incident fatal or non-fatal CHD. Results We identified 4 HDL components with highly replicable across studies; 3 were indices of particle size/composition (extra-large (XL), large (L) and medium/small (MS)), and the other an index of triglycerides (TG) carried in HDL of all sizes. After up to 17 years of follow-up, 4179 incident CHD cases occurred. After adjusting for age, sex, ethnicity, smoking, systolic blood pressure, body mass index, diabetes and LDL-C, higher levels of the XL and MS factors were linked to a reduced risk of CHD (hazard ratio per 1 standard deviation (SD) increase 0.88 [95% CI 0.85, 0.92] and 0.91 [0.87, 0.94]). In contrast, a SD increase in the level of the TG factor was associated with increased risk of CHD (1.10 [1.07, 1.14]). Conclusions and Relevance We found qualitative differences between sub-components of the HDL pathway and the risk of developing CHD. Discovery of the biological determinants of these components, possibly through genetic analysis, will facilitate selection of drug targets and inform trial design. Question Can investigation of sub-components of the high-density lipoprotein (HDL) pathway, measured through nuclear magnetic resonance spectroscopy, point to specific therapeutic targets for prevention of coronary heart disease (CHD)? Findings Using individual-level data from seven longitudinal studies including 28,597 participants and 4197 CHD events, we identified two components of the HDL pathway that were associated with reduced, and one that was associated with increased, risk of CHD. Meaning These sub-components of the HDL pathway, if causally related to atherogenesis, offer a route to more precise therapeutic targets for prevention of CHD. ### Competing Interest Statement VS has participated in a conference trip supported by Novo Nordisk and received a modest honorarium from the same source for participating in an advisory board meeting. JW reports employment with and ownership of shares in GSK. JPC received funding from GSK to conduct methodological work around use of electronic health records and multi-omics for drug-discovery. CJP reports honoraria or grants from MSD, Sanofi/Regeneron, Amgen, and Daiichi-Sankyo. UM has stocks in Abcodia Pvt Ltd, awarded to her by UCL. All other authors have no conflicts to declare. ### Funding Statement The BRHS is supported by British Heart Foundation grant RG/13/16/30528. The BWHHS is supported by British Heart Foundation grant PG/13/66/30442. FINRISK: VS has been supported by the Finnish Foundation for Cardiovascular Research. SABRE was funded at baseline by the UK Medical Research Council and Diabetes UK. Follow-up studies have been funded by the Wellcome Trust (WT 082464), British Heart Foundation (SP/07/001/23603 and CS/13/1/30327) and Diabetes UK (who funded the metabolomics analyses: 13/0004774). NC received support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Support has also been provided at follow-up by the North and West London and Central and East London National Institute of Health Research Clinical Research Networks. UKCTOCS was funded by Medical Research Council (G9901012 and G0801228), Cancer Research UK (C1479/A2884), and Department of Health and The Eve Appeal. UM is supported by funding from the NIHR University College London Hospitals (UCLH) Biomedical Research Centre. MK is supported by the Medical Research Council (R024227) for WH-II infrastructure and data collection; MS is supported by the British Heart Foundation for data analysis. The UCLEB Consortium is supported by the British Heart Foundation (RG/10/12/28456 and SP/13/6/30554) and by the Rosetrees and Stoneygate Trust. ADH is an NIHR Senior Investigator and funded by the UCL Hospitals NIHR Biomedical Research Centre. ### Author Declarations All relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes Any clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript. Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable. Yes Data access is conditional on individual study approval in accordance with existing ethics and governance rules for each study. Summary level data may be made available on request subject to the approval of individual studies.