Comprehensive evaluation of allele frequency differences of MC1R variants across populations

The melanocortin 1 receptor (MC1R), a member of the G protein-coupled receptors superfamily, mediates the response to melanocortins and is currently the best-described contributor to normal pigment variation in humans. A remarkably large number of natural polymorphisms, or variants, of the MC1R gene have been identified in different populations. Some of these variants have been associated with specific hair and skin color phenotypes, the presence of freckling, and melanoma and nonmelanoma skin cancer risk. Interestingly, some MC1R variants have been associated with skin cancer beyond their effects on pigmentation. Although the red hair color variants (RHC variants) have been associated with skin cancer risk in the Celtic population, studies in darkly-pigmented Caucasian populations have demonstrated the importance of non-RHC MC1R variants on skin cancer risk as well. We have reviewed and compared allele frequency differences of MC1R variants across geographic regions. We observed large differences in the distribution of variants across populations, with a prominent difference between lightly and darkly-pigmented individuals. Moreover, among Caucasian groups, there were seven variants (p.V60L, p.V92M, p.D84E, p.R151C, p.R160W, p.R163Q, and p.D294H) with significantly different allele frequencies. Exploring differences in allele frequencies of MC1R variants across populations with varying pigmentation and differing skin cancer risk may improve our understanding of the complex relationship between MC1R, pigmentation, and carcinogenesis.