Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk

Eur Heart J. 2022 May 7;43(18):1731-1739. doi: 10.1093/eurheartj/ehab809.


Aims: Low vitamin D status is associated with a higher risk for cardiovascular diseases (CVDs). Although most existing linear Mendelian randomization (MR) studies reported a null effect of vitamin D on CVD risk, a non-linear effect cannot be excluded. Our aim was to apply the non-linear MR design to investigate the association of serum 25-hydroxyvitamin D [25(OH)D] concentration with CVD risk.

Methods and results: The non-linear MR analysis was conducted in the UK Biobank with 44 519 CVD cases and 251 269 controls. Blood pressure (BP) and cardiac-imaging-derived phenotypes were included as secondary outcomes. Serum 25(OH)D concentration was instrumented using 35 confirmed genome-wide significant variants.We also estimated the potential reduction in CVD incidence attributable to correction of low vitamin D status. There was a L-shaped association between genetically predicted serum 25(OH)D and CVD risk (Pnon-linear = 0.007), where CVD risk initially decreased steeply with increasing concentrations and levelled off at around 50 nmol/L. A similar association was seen for systolic (Pnon-linear = 0.03) and diastolic (Pnon-linear = 0.07) BP. No evidence of association was seen for cardiac-imaging phenotypes (P = 0.05 for all). Correction of serum 25(OH)D level below 50 nmol/L was predicted to result in a 4.4% reduction in CVD incidence (95% confidence interval: 1.8- 7.3%).

Conclusion: Vitamin D deficiency can increase the risk of CVD. Burden of CVD could be reduced by population-wide correction of low vitamin D status.

Keywords: Cardiac-imaging phenotypes; Cardiovascular diseases; Diastolic blood pressure; Non-linear Mendelian randomization; Serum 25-hydroxyvitamin Dconcentration; Systolic blood pressure; Vitamin D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiovascular Diseases* / complications
  • Cardiovascular Diseases* / epidemiology
  • Cardiovascular Diseases* / genetics
  • Humans
  • Mendelian Randomization Analysis
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Vitamin D
  • Vitamin D Deficiency* / complications
  • Vitamin D Deficiency* / epidemiology
  • Vitamin D Deficiency* / genetics
  • Vitamins


  • Vitamins
  • Vitamin D