Is there a causal relationship between vitamin D and melanoma risk? A Mendelian randomization study

Background: Several preclinical studies have identified the antiproliferative effects of 25-hydroxyvitamin D [25(OH)D; vitamin D]. Ultraviolet radiation (UVR) is essential for vitamin D synthesis yet increases the risk of melanoma. Observational studies on the association of vitamin D levels with melanoma risk have reported inconclusive results, and are difficult to interpret owing to the potential confounding from the dual role of UVR.

Objectives: To determine whether there is a causal association between genetically predicted 25(OH)D concentrations and melanoma using a Mendelian randomization (MR) approach.

Methods: We performed MR using summary data from a large genome-wide association study (GWAS) meta-analysis of melanoma risk, consisting of 12 874 cases and 23 203 controls. Five single nucleotide polymorphisms associated with 25(OH)D concentration - rs12785878, rs10741657, rs2282679, rs6013897 and rs116970203 - were selected as instrumental variables. An inverse variance weighted method was used to access the evidence for causality. MR results from the melanoma meta-analysis were combined with results from an MR study based on a melanoma risk GWAS using UK Biobank data.

Results: A 20 nmol L^-1 decrease in 25(OH)D was not associated with melanoma risk [odds ratio (OR) 1·06, 95% confidence interval (CI) 0·95-1·19]. Results from the UK Biobank were concordant with this, with meta-analysis of our and UK Biobank-derived MR causal estimates showing no association (OR 1·02, 95% CI 0·92-1·13 for a 20 nmol L^-1 decrease).

Conclusions: The results suggest that vitamin D levels may not be causally associated with the risk of melanoma. What's already known about this topic? Antitumour activity of vitamin D has been identified in preclinical studies. Observational studies link vitamin D deficiency with an increased risk of a range of cancers. There is a growing public interest for vitamin D supplementation. Observational studies of melanoma are fraught with difficulties because while higher ultraviolet radiation levels increase vitamin D levels, such exposure is also associated with increased melanoma risk. Results from observational studies are inconclusive regarding the effect of vitamin D on melanoma risk. What does this study add? Using Mendelian randomization, an approach to causal inference, which is analogous to a natural randomized controlled trial, we found no causal association between vitamin D levels and melanoma.