Natural hair color and skin cancers: A two-sample Mendelian randomization study.

• The study employs a two-sample Mendelian randomization (MR) approach using genetic instruments to investigate the causal relationship between natural hair color and skin cancers, providing robust evidence for the impact of hair color on skin cancer risk. • Light hair colors, including red, blonde, and light brown, are causally associated with an increased risk of cutaneous melanoma (CM) and keratinocyte skin cancer (KSC), while dark brown hair exhibits an inverse causal relationship with these cancers. Black hair is linked to a decreased KSC risk. • Gender-stratified analyses reveal variations in the effects of hair color on skin cancer risk, highlighting the role of gender in modulating this association. • The study underscores the importance of conducting large-scale MR studies or randomized controlled trials to further explore the underlying mechanisms of the hair color-skin cancer link. Previous observational studies have indicated an association between hair color and the risk of melanoma and keratinocyte skin cancer (KSC); however, different hair colors show inconsistent effects on skin cancers. Here, we conducted a two-sample Mendelian randomization (MR) study to evaluate the causal relationship between natural hair color and skin cancers by using 211 single nucleotide polymorphisms as genetic instruments from a genome-wide meta -analysis of 360,270 individuals of European ancestry. Light hair colors (red, blonde, and light brown) were associated with high levels of cutaneous melanoma (CM) and KSC (CM-inverse variance weighted [IVW] odds ratio [OR]-red: 1.034, 95% confidence interval [CI]: 1.025–1.044, P < 0.001; OR-blonde: 1.008, 95% CI: 1.003–1.014, P = 0.003; OR-light brown: 1.006, 95% CI: 1.002–1.011, P = 0.009; KSC-IVW OR-red: 1.078, 95% CI: 1.053–1.103, P < 0.001; OR-blonde: 1.024, 95% CI: 1.009–1.040, P = 0.002; OR-light brown: 1.018, 95% CI: 1.004–1.033, P = 0.01). However, dark brown hair showed an inverse causal relationship with skin cancers (CM IVW OR: 0.987, 95% CI: 0.984–0.990, P < 0.001; KSC IVW OR: 0.979, 95% CI: 0.970–0.988, P < 0.001). Black hair was associated with a decreased risk of KSC (IVW OR: 0.954, 95% CI: 0.913–0.997, P = 0.036) but showed no causal relationship with CM. The present study provides strong MR evidence of a causal association between hair color and skin cancer. Secondary MR analyses enhances result robustness by replicating findings, exploring gender-specific effects, and providing a more comprehensive understanding of the complex relationship between hair color and skin cancers. More large-scale MR studies or randomized controlled trials are required to further investigate the mechanisms of the association between hair color and skin cancers. [ABSTRACT FROM AUTHOR]