Copyright © 2002 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 70, Issue 3, 770-775, 1 March 2002
doi:10.1086/339076
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A Polymorphism in the Agouti Signaling Protein Gene Is Associated with Human Pigmentation
Peter A. Kanetsky1, 3, 4, 
, 
, Jennifer Swoyer1, 3, Saarene Panossian1, 3, Robin Holmes4, DuPont Guerry2, 4 and Timothy R. Rebbeck1, 3, 4
1 Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia
2 Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia
3 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia
4 Cancer Center, University of Pennsylvania, Philadelphia
Address for correspondence and reprints: Dr. Peter A. Kanetsky, Department of Biostatistics and Epidemiology, 903 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021Abstract
In mice and humans, binding of α-melanocyte–stimulating hormone to the melanocyte-stimulating–hormone receptor (MSHR), the protein product of melanocortin-1 receptor (MC1R) gene, leads to the synthesis of eumelanin. In the mouse, ligation of MSHR by agouti signaling protein (ASP) results in the production of pheomelanin. The role of ASP in humans is unclear. We sought to characterize the agouti signaling protein gene (ASIP) in a group of white subjects, to assess whether ASIP was a determinant of human pigmentation and whether this gene may be associated with increased melanoma risk. We found no evidence of coding-region sequence variation in ASIP, but detected a g.8818A→G polymorphism in the 3′ untranslated region. We genotyped 746 participants in a study of melanoma susceptibility for g.8818A→G, by means of polymerase chain reaction and restriction fragment–length polymorphism analysis. Among the 147 healthy controls, the frequency of the G allele was .12. Carriage of the G allele was significantly associated with dark hair (odds ratio 1.8; 95% confidence interval [CI] 1.2–2.8) and brown eyes (odds ratio 1.9; 95% CI 1.3–2.8) after adjusting for age, gender, and disease status. ASIP g.8818A→G was not associated independently with disease status. This is the first report of an association of ASIP with specific human pigmentation characteristics. It remains to be investigated whether the interaction of MC1R and ASIP can enhance prediction of human pigmentation and melanoma risk.
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