High plasma 25-hydroxyvitamin D and high risk of non-melanoma skin cancer: a Mendelian randomisation study of 97849 individuals Ulrik C. Winsløw, Børge G. Nordestgaard, Shoaib Afzal Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark British Journal of Dermatology. DOI: 10.1111/bjd.16127

Ulrik C. Winsløw, MD. First author

Introduction What’s already known? High plasma 25-hydroxyvitamin 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.

Methods I Population: 103084 individuals recruited from the general population in Denmark Exposures: Plasma 25(OH)D (N=35 298), genetic variants in DHCR7 and CYP2R1 affecting plasma 25(OH)D (N=97 849) Outcomes: Non-melanoma skin cancer ascertained from the national Danish Cancer Registry (N=1569 for observational analyses, N=8643 for genetic analyses)

Methods II Covariates: Age, gender, year of birth, body mass index Follow-up: Median was 7.5 years (range 0.002-31.7)

Design – comparison of designs for estimating causality Randomized trial Mendelian randomization Reproduction Mendel’s 1. and 2. laws Randomization methods Random distribution of alleles Placebo Intervention Normal allele Functional allele Confounding Confounding Confounders evenly distributed Confounders evenly distributed Disease  or  Disease  or  Reverse causation

Results Cumulative incidence of and Hazard ratios for non-melanoma skin cancer by categories of plasma 25- hydroxyvitamin D (25(OH)D)

Results Mean and 95% confidence interval for plasma 25-hydroxyvitamin D (25(OH)D) and risk of non-melanoma skin cancer (odds ratio and 95% confidence interval) across a combined allele score of CYP2R1 and DHCR7.

Results Odds ratio for non-melanoma skin cancer per 20 nmol/L increase in 25(OH)D in observational and genetic analyses.

Discussion & Conclusions What does this study add? We provide the first estimates for the associaiton of 25(OH)D with non-melanoma skin cancer from a Mendelian randomisation study to attain estimates largely free of confounding and reverse causation. Genetically determined high 25(OH)D did not appear to protect against non-melanoma skin cancer. 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 and there does not seem to be a hidden protective effect of plasma 25(OH)D on skin cancer.

Shoaib Afzal, MD, PhD. Senior author

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