Using genetic proxies for lifecourse sun exposure to assess the causal relationship of sun exposure with circulating vitamin d and prostate cancer risk

Background: Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D. Methods: We created a tanning, a skin color, and a freckling score as combinations of single nucleotide polymorphismsthat have been previously associated with these phenotypes.Ahigher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25- dihydroxyvitamin-D) and prostate-specific antigen detected prostate cancer in 3,123 White British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study. Results: The freckling score was inversely associated with 25(OH)D levels [change in 25(OH)D per score unit 0.27; 95% CI, 0.52% to 0.01%], and the tanning score was positively associated with prostate cancer risk (OR 1.05; 95% CI, 1.02-1.09), after adjustment for population stratification and potential confounders. Conclusions: Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer. Impact: The use of pigmentation-related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk.