The Association Between Citrus Consumption and Skin Cancer: An Analysis of Risk and Nutrient-Gene Interaction
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Purpose. In the US, melanoma and non-melanoma skin cancer (NMSC) rates have increased substantially in recent decades. While many skin cancer risk factors have been established, the impact of dietary citrus, which is naturally abundant in photocarcinogenic psoralens, remains enigmatic. The purpose of this research was to investigate associations between citrus consumption and risks of melanoma and NMSC, and to conduct a genome-wide study to identify genetic variants that may modify this association. Methods. Participants from the UK Biobank were leveraged for these analyses. Citrus consumption was collected via five rounds of 24-hour recall questionnaires, with complete citrus data available for n=210,126 participants. Ascertainment of melanoma and NMSC cases were identified by international classification of disease codes via linkage with national registries. Logistic regression was used to estimate odds ratios and 95% confidence intervals for the associations between citrus consumption and skin cancer outcomes. Individual citrus products were assessed for independent associations with skin cancer risk, and established skin cancer risk factors were tested for interaction. Joint 2-degree-of-freedom (df) and 1-df tests were used to assess interaction between total citrus consumption and genetic variants. Results. After controlling for covariates, high total citrus consumption was significantly associated with increased melanoma risk, an association primarily driven by orange and orange juice consumption. Skin color was found to be a significant effect modifier for the association between total citrus consumption and melanoma risk, but only before adjusting for multiple comparisons. No significant associations were observed for high total citrus consumption or consumption of any individual citrus products and NMSC risk. Significant associations for half a serving of citrus consumption and NMSC risk were likely due to chance or confounding. Index SNPs on chromosomes 3, 9, and 16 were significant according to the joint 2-df test, and 7 SNPs on chromosome 16 displayed evidence of a citrus-gene interaction. Conclusion. My analyses provide evidence in support of high citrus consumption significantly increasing risk of melanoma, but not NMSC. I also identified SNPs on AFG3L1P that may modify this association. Future research should further explore these associations, particularly for NMSC and to confirm my genetic findings.