MELANOCORTIN-1 RECEPTOR VARIANTS IN AN IRISH POPULATION

The identification of an association between variants in the human mel anocortin 1 receptor (MC1R) gene and red hair and fair skin, as well a s the relation between variants of this gene and coat color in animals , suggests that the MC1R is an integral control point in the normal pi gmentation phenotype, In order to further define the contribution of M C1R variants to pigmentation in a normal population, we have looked fo r alterations in this gene in series of individuals from a general Iri sh population, in whom there is a preponderance of individuals with fa ir skin type. Seventy-five per cent contained a variant in the MC1R ge ne, with 30% containing two variants. The Arg151Cys, Arg160Trp, and As p294His variants were significantly associated with red hair (p = 0.00 15, p < 0.001, and p < 0.005, respectively). Importantly, no individua ls harboring two of these three variants did not have red hair, althou gh some red-haired individuals only showed one alteration. The same th ree variants were also over-represented in individuals with light skin type as assessed using a modified Fitzpatrick scale. Despite these as sociations many subjects with dark hair/darker skin type harbored MC1R variants, but there was no evidence of any particular association of variants with the darker phenotype, The Asp294His variant was similarl y associated with red hair in a Dutch population, but was infrequent i n red-headed subjects from Sweden. The Asp294His variant was also sign ificantly associated with nonmelanoma skin cancer in a U.K. population . The results show that the Arg151Cys, Arg160Trp, and Asp294His varian ts are of key significance in determining the pigmentary phenotype and response to ultraviolet radiation, and suggest that in many cases the red-haired component and in some cases fair skin type are inherited a s a Mendelian recessive.