The melanocortin-1-receptor gene is the major freckle gene

Ephelides and solar lentigines are different types: of pigmented skin lesio ns. Ephelides appear early, in childhood and are associated with fair skin type and red hair. Solar lentigines appear with increasing age and are a si gn of photodamage. Both lesions are strong risk indicators for melanoma and nonmelanoma skin cancer. Melanocortin-1-receptor (MC1R) gene variants are also associated with fair skin, red hair and melanoma and non-melanoma skin cancer. The purpose of this study was to investigate the relationship betw een MC1R gene variants, ephelides and solar lentigines. In a large case-con trol study, patients with melanoma and non-melanoma skin cancer and subject s without a history of skin cancer were studied. In all participants, the p resence of ephelides in childhood and solar lentigines by physical examinat ion was assessed according to strict definitions. The entire coding sequenc e of the MC1R gene was analyzed by single-strand conformation polymorphism analysis followed by sequence analyses. Carriers of one or two MC1R gene va riants had a 3- and 11-fold increased risk of developing ephelides, respect ively (both P < 0.0001), whereas the risk of developing severe solar lentig ines was increased 1.5- and 2-fold (P = 0.035 and P < 0.0001), respectively . These associations were independent of skin type and hair color, and were comparable in patients with and without a history of skin cancer. The popu lation attributable risk for ephelides to MC1R gene variants was 60%, i.e. 60% of the ephelides in the population was caused by MC1R gene variants. A dosage effect was found between the degree of ephelides and the number of M C1R gene variants. As nearly all individuals with ephelides were carriers o f at least one MC1R gene variant, our data suggest that MC1R gene variants are necessary to develop ephelides. The results of the study also suggest t hat MC1R gene variants play a role, although less important, in the develop ment of solar lentigines.