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

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.