Quantitative Measures of the Effect of the Melanocortin 1 Receptor on Human Pigmentary Status11Presented in part at ESDR Geneva 2002, Naysmith L, Ha T, Waterston K, et al: Melanocortin 1 receptor accounts for 50% of variation in a Northern European dataset. J Invest Dermatol 119:758, 2002 (abstr).

Abstract

Variation in human hair and skin color is the most striking visible aspect of human genetic variation. The only gene known to exert an effect on pigmentary within the normal population is the melanocortin-1 receptor (MC1R). Previous studies have used a Mendelian framework to relate MC1R genotype to phenotype, by measuring pigmentary status using categorical scales. Such approaches are inadequate. We report results using direct measures of hair color using objective colorimetric dimensions and HPLC determined hair melanins. We have linked MC1R genotype with chemical measures of melanin quantity and type and objective phenotype measures of color. MC1R genotype was predictive of hair melanin expressed as the ratio of the loge of eumelanin to pheomelanin ratio, with a dosage effect evident: MC1R homozygote mean, 1.46; heterozygote, 4.44; and wild type, 5.81 (p<0.001). Approximately 67% of the variance in this model could be accounted for in terms of MC1R genotype. There was also a relation between MC1R status and hair color, most prominently for the b* axis (p<0.001), but also for the a* and L* scales (L*a*b*, CIE). We show for one of the most polymorphic human traits that it is possible to demonstrate meaningful relations between various physical characteristics: DNA sequence diversity, hair-wavelength-specific reflectance patterns, and chemical melanin assays.

Host Phenotype Characteristics and MC1R in Relation to Early-Onset Basal Cell Carcinoma

“…Of note, one small case-control study with a heterogeneous case group enrolled on the basis of having either familial BCC, multiple BCC, BCC with another cancer, or BCC before age 40, observed a seven-fold increased risk of BCC with two MC1R variants (Liboutet et al , 2006). Similar to our findings, MC1R variants have been associated with lighter pigment phenotypes in numerous studies (Bastiaens et al , 2001; Box et al , 2001; Dwyer et al , 2004; Han et al , 2006; Kanetsky et al , 2004; Kennedy et al , 2001; Koppula et al , 1997; Naysmith et al , 2004; Palmer et al , 2000; Smith et al , 1998; Valverde et al , 1995). …”

“…Among pigment-related factors, the melanocortin 1 receptor gene ( MC1R ), which encodes a protein that binds melanocyte-stimulating hormone and regulates skin and hair pigmentation (Valverde et al , 1995), has received considerable attention and has been associated with an increased risk of melanoma and BCC (reviewed in (Scherer and Kumar, 2010)). Even though MC1R variants are related to light pigmentation phenotypes (Bastiaens et al , 2001; Box et al , 2001; Dwyer et al , 2004; Han et al , 2006; Kanetsky et al , 2004; Kennedy et al , 2001; Koppula et al , 1997; Naysmith et al , 2004; Palmer et al , 2000; Smith et al , 1998; Valverde et al , 1995), there seems to be an effect of genotype independent of phenotype on both BCC (Bastiaens et al , 2001; Box et al , 2001; Dwyer et al , 2004; Han et al , 2006; Liboutet et al , 2006; Scherer et al , 2008) and melanoma (Dwyer et al , 2004; Kanetsky et al , 2010; Kennedy et al , 2001; Landi et al , 2005; Palmer et al , 2000). These findings, in combination with other emerging evidence from epidemiologic, clinical, and basic science research, indicate BCC may be more similar to melanoma than squamous cell carcinoma (SCC) in etiology (Dessinioti et al , 2010; Madan et al , 2010).…”

A Novel Role for Mc1r in the Parallel Evolution of Depigmentation in Independent Populations of the Cavefish Astyanax mexicanus

“…In particular, in humans the R160W Mc1r variant (homologous to position 164 in Astyanax ) is one of two alleles strongly associated with the inheritance of red hair and pale skin [26],[27],[34],[35]. Mutations of this amino acid have been demonstrated to convey diminished receptor function [21], [36]–[38]. Therefore, we reasoned that the identical charge-changing amino acid mutation at the homologous position would be extremely likely to cause diminished function of Mc1r protein in the Yerbaniz and Japonés populations of cavefish, explaining the presence of the brown mutation in these fish.…”

Cutaneous malignant melanoma incidences analyzed worldwide by sex, age, and skin type over personal Ultraviolet-B dose shows no role for sunburn but implies one for Vitamin D3

“…Recently, scientists confirmed the human variants of the MC1R red hair gene dramatically increase the risk for getting CMM independent of UVR exposure 70 . Furthermore, both homozygote and heterozygote red hair melanocortin-1-receptor variants are sensitive to UVR exposure 71 and have eumelanin to pheomelanin ratios of only 1.46 and 4.44, respectively, while wild types have 5.81 (p < 0.001) 72 . These findings highlight the fact that people with dark hair and certain melanocortin-1-receptor variants can also get CMM 73 .…”