Serum 25-Hydroxyvitamin D and Cancer Risk: A Systematic Review of Mendelian Randomization Studies

Nutrients. 2023 Jan 13;15(2):422. doi: 10.3390/nu15020422.


Epidemiological studies suggest that higher serum 25-hydroxyvitamin D is associated with lower risk for several cancers, including breast, prostate, colorectal, and lung cancers. To mitigate confounding, genetic instrumental variables (IVs) have been used to estimate causal associations between 25-hydroxivtamin D and cancer risk via Mendelian randomization (MR). We provide a systematic review of 31 MR studies concerning 25-hydroxyvitamin D and cancer incidence and mortality identified from biomedical databases. MR analyses were conducted almost exclusively in European-ancestry populations and identified no statistically significant associations between higher genetically predicted 25-hydroxyvitamin D and lower risk for total cancer or colorectal, breast, prostate, lung, or pancreatic cancers. In recent studies including ≥80 genetic IVs for 25-hydroxyvitamin D, null associations were reported for total cancer (odds ratio [95% confidence interval] per 1-standard deviation increase: 0.98 [0.93-1.04]), breast (1.00 [0.98-1.02]), colorectal (0.97 [0.88-1.07]), prostate (0.99 [0.98-1.01]), and lung cancer (1.00 [0.93-1.03]). A protective association was observed for ovarian cancer in the Ovarian Cancer Association Consortium (0.78 [0.63-0.96] per 20 nmol/L increase, p-trend = 0.03), but not in the UK Biobank (1.10 [0.80-1.51]). Null associations were reported for other tumor sites (bladder, endometrium, uterus, esophagus, oral cavity and pharynx, kidney, liver, thyroid, or neural cells). An inconsistent protective association for cancer-specific mortality was also observed. Results from MR analyses do not support causal associations between 25-hydroxyvitamin D and risk for cancer incidence or mortality. Studies including non-White populations may be valuable to understand low 25-hydroxyvitamin D as a modifiable risk factor in populations with a higher risk of common cancers, including African ancestry individuals.

Keywords: African-American; Mendelian randomization; cancer; vitamin D.

Publication types

  • Systematic Review
  • Review

MeSH terms

  • Calcifediol
  • Colorectal Neoplasms* / genetics
  • Female
  • Humans
  • Lung Neoplasms* / genetics
  • Male
  • Mendelian Randomization Analysis / methods
  • Ovarian Neoplasms* / genetics
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Vitamin D


  • 25-hydroxyvitamin D
  • Vitamin D
  • Calcifediol