Polyunsaturated Fatty Acid Levels and the Risk of Keratinocyte Cancer: A Mendelian Randomization Analysis

Background: Keratinocyte cancer is the commonest cancer, imposing a high economic burden on the health care system. Observational studies have shown mixed associations between polyunsaturated fatty acids (PUFA) and keratinocyte cancer, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We explored whether genetically predicted PUFA levels are associated with BCC and SCC risks. Methods: We conducted a two-sample Mendelian randomization study using PUFA level genome-wide association studies (GWAS) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n > 8,000), and the meta-analysis GWASs from UKB, 23andMe, and Qskin for BCC (n = 651,138) and SCC (n = 635,331) risk. Results: One SD increase in genetically predicted levels of linoleic acid [OR = 0.94, 95% confidence interval (CI) = 0.91–0.97, P = 1.4 × 10–4] and alpha-linolenic acid (OR = 0.91, 95% CI = 0.86–0.96, P = 5.1 × 10–4) was associated with a reduced BCC risk, while arachidonic acid (OR = 1.04, 95% CI = 1.02–1.06, P = 3.2 × 10–4) and eicosapentaenoic acid (OR = 1.10, 95% CI = 1.04–1.16, P = 1.5 × 10–3) were associated with an increased BCC risk. Conclusions: Higher genetically predicted levels of linoleic acid and alpha-linolenic acid were associated with a reduced BCC risk, but arachidonic acid and eicosapentaenoic acid were associated with a higher BCC risk. Impact: PUFA-related diet and supplementation could influence BCC etiology.