Basal cell carcinoma genetic susceptibility increases the rate of skin ageing: a Mendelian randomization study

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Abstract Background Onset of basal cell carcinoma (BCC) is connected to skin ageing, but it is unclear whether higher BCC genetic susceptibility drives skin ageing. Objectives To investigate whether loci increasing genetic susceptibility to BCC also drive multiple features of skin ageing, independently of confounding factors, using Mendelian randomization. Methods A Mendelian randomization study was conducted in older adults from the Leiden Longevity Study (N = 604). A total of 25 BCC loci, selected based on a published genome‐wide association study on BCC (P‐value < 5 × 10−8), were used as genetic instruments for the calculation of a standardized (mean = 0, SD = 1) weighted BCC genetic risk score. Based on facial photographs, we determined perceived age, and skin wrinkling and pigmented spot grading. Results A higher BCC genetic risk score was associated with a higher perceived age (adjusted for chronological age and sex) of 0.88 years (95% CI: 0.44, 1.31; P‐value = 7.1e−5), greater wrinkling by 0.14 grades (95% CI: 0.05, 0.23; P‐value = 2.3e−3), and greater pigmented spots by 0.17 grades (95% CI: 0.08, 0.25; P‐value = 1.1e−4). These findings were weakened but still present after exclusion of gene variants in MC1R and IRF4 which have potential pleiotropic effects. Conclusions Mechanisms influenced by genetic loci increasing susceptibility to BCC also drive skin ageing suggesting shared biology and shared targets for interventions.

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