High plasma 25-hydroxyvitamin D and high risk of non-melanoma skin cancer: a Mendelian randomisation study of 97849 individuals

Abstract

Background

High plasma 25-hydroxyvitamin D (25 (OH)D) concentration has been associated observationally with high risk of non-melanoma skin cancer, while many studies suggest that vitamin D could have a protective effect on cancer. The true association between vitamin D and risk of skin cancer remains unclear.

Objectives

In this Mendelian randomisation study we tested the hypothesis that genetically high plasma 25(OH)D protects against non-melanoma skin cancer.

Methods

We included 103084 individuals from the Danish general population, of whom 35 298 had plasma 25(OH)D measured and 97849 were genotyped for four genetic variants near the DHCR7 and CYP2R1 genes associated with 25(OH)D concentrations. We tested the association between plasma 25(OH)D levels and non-melanoma skin cancer observationally, and between genetically determined 25(OH)D levels and non-melanoma skin cancer through an instrumental variable approach.

Results

Multivariable adjusted hazard ratios of non-melanoma skin cancer were 3.27 (95%CI: 2.22;4.84) for plasma 25(OH)D≥50 nmol/L versus <25 nmol/L. Genetic variants around DHCR7 and CYP2R1 genes were associated with up to 8.2 nmol/L higher 25(OH)D concentrations (F=314). The odds ratio for a genetically determined 20 nmol/L higher plasma 25(OH)D was 1.11 (0.91-1.35) for non-melanoma skin cancer, with a corresponding observational multivariable adjusted odds ratio of 1.13 (1.10-1.17).

Conclusion

Genetically determined high 25(OH)D did not appear to protect against non-melanoma skin cancer, while high plasma 25(OH)D concentrations were associated with high risk of non-melanoma skin cancer in observational analysis. Thus, the observational association likely reflects confounding by sun exposure rather than causality.

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