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

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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.

Original languageEnglish
Pages (from-to)1731-1739
Number of pages9
JournalEuropean heart journal
Issue number18
Publication statusPublished or Issued - 7 May 2022


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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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