Potential causal associations of serum 25-hydroxyvitamin D with lipids: a Mendelian randomization approach of the HUNT study
Observational studies have shown consistent associations between higher circulating 25-hydroxyvitamin D [25(OH)D] levels and favorable serum lipids. We sought to investigate if such associations were causal. A Mendelian randomization (MR) study was conducted on a population-based cohort comprising 56,435 adults in Norway. A weighted 25(OH)D allele score was generated based on vitamin D-increasing alleles of rs2282679, rs12785878 and rs10741657. Linear regression analyses of serum lipid levels on the allele score were performed to assess the presence of causal associations of serum 25(OH)D with the lipids. To quantify the causal effects, the inverse-variance weighted method was used for calculating MR estimates based on summarized data of individual single-nucleotide polymorphisms. The MR estimate with 95% confidence interval (CI) represents percentage difference in the lipid level per genetically determined 25 nmol/L increase in 25(OH)D. The 25(OH)D allele score demonstrated a clear association with high-density lipoprotein (HDL) cholesterol (p = 0.007) but no association with total or non-HDL cholesterol or triglycerides (p ≥ 0.27). The MR estimate showed 2.52% (95% CI 0.79–4.25%) increase in HDL cholesterol per genetically determined 25 nmol/L increase in 25(OH)D, which was stronger than the corresponding estimate of 1.83% (95% CI 0.85–2.81%) from the observational analysis. The MR estimates for total cholesterol (0.60%, 95% CI − 0.73 to 1.94%), non-HDL cholesterol (0.04%, 95% CI − 1.79 to 1.88%) and triglycerides (− 2.74%, 95% CI − 6.16 to 0.67%) showed no associations. MR analysis of data from a population-based cohort suggested a causal and positive association between serum 25(OH)D and HDL cholesterol.
KeywordsCholesterol High-density lipoprotein (HDL) Lipid Low-density lipoprotein (LDL) Mendelian randomization Serum 25-hydroxyvitamin D [25(OH)D] Single-nucleotide polymorphisms Triglycerides Vitamin D
The Nord-Trøndelag Health Study (HUNT) is a collaboration between the HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU—Norwegian University of Science and Technology), the Nord-Trøndelag County Council, and the Norwegian Institute of Public Health. The authors especially thank the HUNT Research Centre laboratory personnel for the measurement of serum 25(OH)D and the K. G. Jebsen Center for Genetic Epidemiology for the genotyping data.
XMM and YQS contributed to the study design. YQS conducted statistical analyses. XMM wrote the initial draft of the manuscript. XMM, VV, NAS, YC, AL and YQS contributed to interpretation of results and writing the final draft of the manuscript. All authors approved the final version of the manuscript.
This work was supported by “Nasjonalforeningen for folkehelsen”, by The Norwegian Cancer Society (Project ID 5769155-2015) and The Research Council of Norway “Gaveforsterkning”.
Compliance with ethical standards
Conflict of interest
XMM reports grant from “Nasjonalforeningen for folkehelsen” and YQS reports grant from The Norwegian Cancer Society during the conduct of the study. All other authors declare that they have no conflict of interest.
The interpretation and reporting of data are sole responsibility of the authors, and no endorsement by the grant supporters is intended nor should be inferred.
Ethics approval and consent to participate
The study was approved by the Regional Committee for Medical and Health Research Ethics. All participants gave their informed consent for participation in HUNT.
- 4.Challoumas D. Vitamin D supplementation and lipid profile: what does the best available evidence show? Atherosclerosis. 2014;235(1):130–9. https://doi.org/10.1016/j.atherosclerosis.2014.04.024.CrossRefGoogle Scholar
- 10.Boekholdt SM, Arsenault BJ, Hovingh GK, et al. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis. Circulation. 2013;128(14):1504–12. https://doi.org/10.1161/circulationaha.113.002670.CrossRefGoogle Scholar
- 34.Swart KM, Lips P, Brouwer IA, et al. Effects of vitamin D supplementation on markers for cardiovascular disease and type 2 diabetes: an individual participant data meta-analysis of randomized controlled trials. Am J Clin Nutr. 2018;107(6):1043–53. https://doi.org/10.1093/ajcn/nqy078.CrossRefGoogle Scholar
- 36.Haase CL, Tybjaerg-Hansen A, Qayyum AA, Schou J, Nordestgaard BG, Frikke-Schmidt R. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab. 2012;97(2):E248–56. https://doi.org/10.1210/jc.2011-1846.CrossRefGoogle Scholar