title: Assessment of polymorphic variants in the melanocortin-1 receptor gene with cutaneous pigmentation using an evolutionary approach.
abstract: The melanocortin-1 receptor gene (MC1R) encodes a membrane-bound receptor protein that is central to melanin synthesis. The coding region of MC1R is highly polymorphic and associations of variants with pigmentation phenotypes and risk for cutaneous neoplasms have been reported. We sought to determine the distribution and frequency of MC1R variants and their relationship to pigmentation characteristics in 179 Caucasian controls from the United States. One hundred thirty-five (75.4%) subjects carried one or more variants, and we determined that carriage of the previously designated "red hair color" (RHC) alleles, R151C, R160W, and D294H was strongly associated with fair pigmentation phenotypes including light hair and eye color, tendency to burn, decreased tendency to tan, and freckling. We used SIFT software to define MC1R protein positions that were predicted intolerant to amino acid substitutions; detected variants that corresponded to intolerant substitutions were D84E, R142H, R151C, I155T, R160W, and D294H. Carriage of one or more of these putative functionally important variants or the frameshift variant ins86A was significantly associated with fair pigmentation phenotypes. Analyses limited to carriage of ins86A and the three non-RHC alleles identified by SIFT were attenuated and no longer reached statistical significance. This is the first study to describe MC1R variants among control subjects from the U.S. Our results indicate that the frequency of variants is similar to that previously observed among non-U.S. Caucasians. Risk variants defined by either the published literature or by evolutionary criteria are strongly and significantly associated with all fair pigmentation phenotypes that were measured.
authors.affiliation: Department of Biostatistics and Epidemiology, Division of Hematology-Oncology, Center for Clinical Epidemiology and Biostatistics and Epidemiology, University of Pennsylvania, 903 Blockley Hall, Philadelphia, PA 19104-6021. pkanetsk@cceb.med.upenn.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
authors.forename: Fan
authors.initials: F
authors.lastname: Ge
authors.forename: Derek
authors.initials: D
authors.lastname: Najarian
authors.forename: Jennifer
authors.initials: J
authors.lastname: Swoyer
authors.forename: Saarene
authors.initials: S
authors.lastname: Panossian
authors.forename: Lynn
authors.initials: L
authors.lastname: Schuchter
authors.forename: Robin
authors.initials: R
authors.lastname: Holmes
authors.forename: DuPont
authors.initials: D
authors.lastname: Guerry
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D016001:Confidence Intervals; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011336:Probability; D011379:Prognosis; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D012680:Sensitivity and Specificity; D012878:Skin Neoplasms / Q000235:genetics*; D012880:Skin Pigmentation / Q000235:genetics
chemical_list: D044102:Receptor, Melanocortin, Type 1