A polymorphism in the agouti signaling protein gene is associated with human pigmentation

Am J Hum Genet. 2002 Mar;70(3):770-5. doi: 10.1086/339076. Epub 2002 Feb 6.


In mice and humans, binding of alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging
  • Agouti Signaling Protein
  • Eye Color / genetics
  • Female
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease
  • Genotype
  • Hair Color / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Male
  • Melanoma / genetics
  • Odds Ratio
  • Phenotype
  • Pigmentation / genetics*
  • Polymorphism, Genetic / genetics*
  • Proteins / genetics*
  • Sex Characteristics
  • Skin Pigmentation / genetics
  • White People / genetics


  • Agouti Signaling Protein
  • Intercellular Signaling Peptides and Proteins
  • Proteins