Fibroblast Growth Factor-23 and Risk of Cardiovascular Diseases: a Mendelian Randomisation study

Fibroblast growth factor 23 (FGF-23) is associated with a range of cardiovascular and non-cardiovascular diseases in conventional epidemiological studies, but substantial residual confounding may exist. Mendelian randomisation approaches can help control for such confounding. SCALLOP consortium data on 19,195 participants were used to generate an FGF-23 genetic score. Data from 337,448 UK Biobank participants were used to estimate associations between higher genetically-predicted FGF-23 concentration and the odds of any atherosclerotic cardiovascular disease (n=26,266 events), of any non-atherosclerotic cardiovascular disease (n=12,652), and of non-cardiovascular diseases previously linked to FGF-23. Measurements of carotid intima-media thickness (CIMT) and left ventricular mass (LVM) were available in a subset. Associations with cardiovascular outcomes were also tested in three large case-control consortia: CARDIOGRAMplusC4D (coronary artery disease, n=181,249 cases), MEGASTROKE (stroke, n=34,217), and HERMES (heart failure, n=47,309). We identified 34 independent variants for circulating FGF-23 which formed a validated genetic score. There were no associations between genetically-predicted FGF-23 and any of the cardiovascular or non-cardiovascular outcomes. In UK Biobank, the odds ratio for any atherosclerotic cardiovascular disease per 1-SD higher genetically-predicted logFGF-23 was 1.03 (95% confidence interval [CI] 0.98-1.08), and for any non-atherosclerotic cardiovascular disease was 1.01 (0.94-1.09). The odds ratios in the case-control consortia were 1.00 (0.97-1.03) for coronary artery disease, 1.01 (0.95-1.07) for stroke, and 1.00 (0.95-1.05) for heart failure. In those with imaging, logFGF-23 was not associated with CIMT or LVM index. This suggests that previously reported observational associations of FGF-23 with risk of atherosclerotic and non-atherosclerotic cardiovascular diseases are unlikely to be causal. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by UK-MRC, Kidney Research UK, NIHR and the British Heart Foundation ### 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: The committee of the UK Biobank gave approval for use of their data in this work (under application number 15595), under the umbrella of their own ethical approval from the NHS Northwest - Haydock Research Ethics committee (approval number: 16/NW/0274). The ORIGIN randomised controlled trial (rationale and protocol available at doi: 10.1016/j.ahj.2007.09.009) was a multi-centre international randomised trial with ethical approval from the local ethical committees in each participating centre. The HERMES consortium is a collaboration of 57 cohort studies across Europe and North America. Participants in each cohort were recruited under the ethical approvals of each respective study. Further details can be found in the HERMES design paper at doi: 10.1002/ehf2.13517. The MEGASTROKE consortium is a collaboration of 12 cohort studies from across the globe. Participants in each cohort were recruited under the ethical approval of each respective study. Further details can be found in the initial MEGASTROKE publication at doi: 10.1038/s41588-018-0058-3. The CARDIOGRAMplusC4D data used in the present study comprises data from the CARDIOGRAM consortium (collaboration of 14 studies, doi: 10.1161/CIRCGENETICS.109.899443), the C4D study (a collaboration of 4 cohort studies doi: 10.1038/ng.782) and 8 further cohort studies/trials (doi: 10.1101/2021.05.24.21257377). Each of these studies recruited their participants in accordance with their own ethical approvals. 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 All data produced in the present study are available upon reasonable request to the authors