Investigating the relationship of serum vitamin D levels with blood pressure and hypertension risk in The HUNT Study: Using traditional observational and Mendelian randomization approaches

Background: Limited studies have triangulated the relationship between serum vitamin D [25(OH)D] levels and systolic blood pressure (SBP), diastolic blood pressure (DBP) or hypertension risk using traditional observational and Mendelian randomization (MR) approaches. Methods and results: Data were obtained from the Norwegian Trøndelag Health Study (HUNT). A cross-sectional study was performed among 5854 participants from HUNT2. Among them, 3592 participants were followed over 11 years for a prospective analysis. Furthermore, a one-sample MR was conducted with 86,324 participants from HUNT. An externally weighted genetic risk score based on 19 genetic variants for 25(OH)D was used as instrument and the Wald ratio method was applied to evaluate causal associations. Additionally, two-sample MR were performed using updated publicly available data. Our cross-sectional analyses showed a 25 nmol/L increase in 25(OH)D was associated with a 1.73 mmHg decrease in SBP (95 % CI -2.46 to -1.01), a 0.91 mmHg decrease in DBP (95% CI -1.35 to -0.47) and 19% lower prevalence of hypertension (OR 0.81, 95% CI 0.74 to 0.90) after adjusting for important confounders. However, these associations disappeared in prospective analyses. Both one-sample and two-sample MR results suggested no causal associations. Conclusions: Cross-sectional findings of inverse associations between serum 25(OH)D levels and blood pressure or hypertension were not supported by results from the prospective and MR analyses, suggesting no causal links. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement LJ was supported by funding from the collaboration partner between the Liaison Committee for Education, Research and Innovation in Central Norway and Central Norway Regional Health Authority (project ID: 30320). YQS was supported by a researcher grant from The Liaison Committee for Education, Research and Innovation in Central Norway (project ID: 2018/42794). MD was supported by research funding from the Norwegian Women?s Public Health Association (N.K.S.: 40014) and top-up funding from the collaboration partner between St Olav hospital and NTNU, Norwegian University of Science and Technology. BMB works in a research unit funded by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU; The Liaison Committee for Education, Research and Innovation in Central Norway. None of the funding sources was involved in any aspect of the study design, conduct, analyses, interpretation of data, or writing the report. ### 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 study was approved by the Regional Committee for Medical and Health Research Ethics of central Norway (application number:434217). All participants signed informed written consent on participation in HUNT. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. 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 Data from the HUNT Study is available on request to the HUNT Data Access Committee (hunt@ medisin.ntnu.no) when is used in research projects. The HUNT data access information describes the policy regarding data availability (https://www.ntnu.edu/hunt/data).