Copyright © 2000 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 66, Issue 1, 176-186, 1 January 2000
doi:10.1086/302711
Melanocortin-1 Receptor Polymorphisms and Risk of Melanoma: Is the Association Explained Solely by Pigmentation Phenotype?
James S. Palmer1, 2, *, David L. Duffy2, *, Neil F. Box1, *, Joanne F. Aitken2, Louise E. O'Gorman2, Adele C. Green2, Nicholas K. Hayward2, Nicholas G. Martin2 and Richard A. Sturm1, 
, 
1 Centre for Molecular and Cellular Biology, University of Queensland, Brisbane, Australia
2 Queensland Institute of Medical Research and Joint Genetics Program, University of Queensland, Brisbane, Australia
Address for correspondence and reprints: Dr. Richard A. Sturm, Centre for Molecular and Cellular Biology, University of Queensland, Brisbane, QLD 4072, Australia* The first three authors contributed equally to this work and should be considered joint first authors.
Abstract
Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk, controlled for pigmentation phenotype. We report the occurrence of five common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals—and their relationship to such other risk factors as skin, hair, and eye color; freckling; and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of the individuals with CMM, whereas only 56% of the control individuals carried at least one variant (P<.001), a finding independent of strength of family history of melanoma. Three active alleles (Arg151Cys, Arg160Trp, and Asp294His), previously associated with red hair, doubled CMM risk for each additional allele carried (odds ratio 2.0; 95% confidence interval 1.6–2.6). No such independent association could be demonstrated with the Val60Leu and Asp84Glu variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. We conclude that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype and that these alleles may also negate the protection normally afforded by darker skin coloring in some members of this white population.
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