Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color

Individuals carrying melanocortin 1 receptor gene variants have an increase d risk for the development of cutaneous melanoma. Melanocortin 1 receptor g ene variants are also associated with other risk factors for melanoma such as fair skin and red hair. We evaluated the relationship of melanocortin 1 receptor gene variants, fair skin, red hair and the development of melanoma in 123 patients with cutaneous melanoma and 385 control subjects. To analy ze the association between melanocortin 1 receptor gene variants and skin t ype or hair color we also made use of 453 patients with nonmelanoma skin ca ncer. We analyzed the coding sequence of the melanocortin 1 receptor gene r egion by single-stranded conformation polymorphism analysis, followed by DN A sequence analysis. Risk of melanoma dependent on the various melanocortin 1 receptor variant alleles was estimated by exposure odds ratios. The anal yses of all different melanocortin 1 receptor gene variants combined, showe d that the presence of melanocortin 1 receptor gene variants amounted to a higher melanoma risk, which, in stratified analyses, was independent of ski n type and hair color. The odds ratios after adjusting for skin type were 3 .6 (95% CI 1.7-7.2) for two variants and 2.7 (95% CI 1.5-5.1) for one varia nt, respectively. Compound heterozygotes and homozygotes for the Va160Leu, Va192Met, Arg142His, Arg151Cys, Arg160Trp, Arg163Gln, and His260Pro variant s had odds ratios of about 4 to develop melanoma, whereas heterozygotes for these variants had half the risk. The presence of the melanocortin 1 recep tor gene variant Asp84Glu appeared to impose the highest risk for cutaneous melanoma with odds ratios of 16.1 (95% CI 2.3-139.0) and 8.1 (95% CI 1.2-5 5.9) in compound heterozygotes and heterozygotes, respectively. The broad c onfidence intervals, when the different variants were analyzed separately, however, do not allow drawing definite conclusions about the magnitude of t hese risks. Of the more frequently occurring melanocortin 1 receptor varian t alleles the Asp84Glu, Arg142His, Arg151Cys, Arg160Trp, His260Pro, and Asp 294His variants were strongly associated with both fair skin and red hair. The Va160Leu, Va192Met, and Arg163Gln variant alleles, however, were only w eakly or not associated with fair skin type and/or red hair, which further illustrates the finding that skin type, hair color, and melanoma are indepe ndent outcomes of the presence of melanocortin 1 receptor gene variants. We conclude that numerous melanocortin 1 receptor variants predispose to cuta neous melanoma and that possibly the Asp84Glu variant confers the highest r isk. This predisposition is largely independent of skin type and hair color .