Por favor, use este identificador para citar o enlazar este ítem:
http://conacyt.repositorioinstitucional.mx/jspui/handle/1000/269| High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease | |
| Dipender Gill Mika Ala-Korpela Claudia Langenberg Adam Butterworth Stephen Burgess Verena Zuber Leonardo Bottolo | |
| Novel Coronavirus | |
| Acceso Abierto | |
| Atribución | |
| 10.1101/2020.02.10.20021691 | |
| Background: Genetic variants can be used to prioritize risk factors as potential therapeutic targets via Mendelian randomization (MR). An agnostic statistical framework using Bayesian model averaging (MR-BMA) can disentangle the causal role of correlated risk factors with shared genetic predictors. Here, our objective is to identify lipoprotein measures as mediators between lipid-associated genetic variants and coronary artery disease (CAD) for the purpose of detecting therapeutic targets for CAD. Methods: As risk factors we consider 30 lipoprotein measures and metabolites derived from a high-throughput metabolomics study including 24,925 participants. We fit multivariable MR models of genetic associations with CAD estimated in 453,595 participants (including 113,937 cases) regressed on genetic associations with the risk factors. MR-BMA assigns to each combination of risk factors a model score quantifying how well the genetic associations with CAD are explained. Risk factors are ranked by their marginal score and selected using false discovery rate (FDR) criteria. We perform sensitivity and replication analyses varying the dataset for genetic associations with CAD. Results: In the main analysis, the top combination of risk factors ranked by the model score contains apolipoprotein B (ApoB) only. ApoB is also the highest ranked risk factor with respect to the marginal score (FDR< 0.005). Additionally, ApoB is selected in all replication analyses. No other measure of cholesterol or triglyceride is consistently selected otherwise. Conclusions: Our agnostic genetic investigation prioritizes ApoB across all datasets con- sidered, suggesting that ApoB, representing the total number of hepatic-derived lipoprotein particles, is the primary lipid determinant of CAD. ### Competing Interest Statement A.S.B. has received grants outside of this work from AstraZeneca, Biogen, Bioverativ, Merck, Novartis and Sanofi, and personal fees from Novartis. All other authors declare no competing interests. ### Funding Statement This work was supported by the UK Medical Research Council (MC$_$UU$_$00002/7). S.B. and V.Z. are supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z). M.A.K is supported by a research grant from the Sigrid Juselius Foundation, Finland. This work was supported by core funding from: the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]$^{star}$ and Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 This study is based on publicly available data. | |
| Cold Spring Harbor Laboratory Press | |
| 2020 | |
| Preimpreso | |
| https://www.medrxiv.org/content/10.1101/2020.02.10.20021691v1 | |
| Inglés | |
| VIRUS RESPIRATORIOS | |
| Aparece en las colecciones: | Artículos científicos |
Cargar archivos:
| Fichero | Tamaño | Formato | |
|---|---|---|---|
| High throughput.pdf | 1.2 MB | Adobe PDF | Visualizar/Abrir |