A Polymorphism in the Agouti Signaling Protein Gene Is Associated with Human Pigmentation

Abstract

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.

Genetics of melanoma predisposition

“…The most noticeable feature of this study was the much lower frequency of nullizygotes in the Spanish controls compared to that observed in other Caucasian control populations. In the most recent study of GST polymorphisms and melanoma risk, Kanetsky et al (2001) found no significant increase in frequency of either GSTM1 or GSTT1 nullizygotes in the melanoma cohort compared with controls from Pennsylvania. However, when they stratified by pigmentation characteristics they found that among individuals with red or blond hair cases were 2.2-fold more likely (95% CI, 1.2-4.2) than controls to be GSTM1 null, and 9.5-fold more likely (95% CI, 1.2-73.0) to be nullizygous for both GSTM1 and GSTT1.…”

Coat colours in the Massese sheep breed are associated with mutations in the agouti signalling protein (ASIP) and melanocortin 1 receptor (MC1R) genes

“…Mutations at this locus affecting or associated with coat colours or skin pigmentation have been also identified in other species. These mutations can affect both coding (rat, Kuramoto et al, 2001;horse, Rieder et al, 2001;dog, Kerns et al, 2004;Berryere et al, 2005;cat, Eizirik et al, 2003;fox, Vå ge et al, 1997;rabbit, Fontanesi et al, 2010b) and non-coding/regulatory regions (human: Kanetsky et al, 2002;cattle: Girardot et al, 2006). In sheep, at least three mutations were suggested to cause the non-agouti recessive black coat colour (Norris and Whan, 2008;Royo et al, 2008;Gratten et al, 2010): a 5 bp deletion in exon 2 (g.100-105delAGGAA, denoted D 5 ), a missense mutation in exon 4 (g.5172T.A or p.C126S) and a regulatory mutation only indirectly deduced but not yet characterized.…”

Gene–gene interactions contribute to eye colour variation in humans

“…9 Several genes were associated with various pigment traits long before the genome-wide association study era. [10][11][12][13][14][15][16] However, it is important to note that-unlike in the case of testing for many complex diseases 17 genome-wide association study has been particularly effective in association testing for human pigmentation and has confirmed already known, and revealed multiple new polymorphisms and loci involved in determination of human pigmentation. [18][19][20][21] This has been particularly striking in the case of variation in eye colour, which is assessed to be 50% explained by known polymorphisms.…”