The Genetics of Sun Sensitivity in Humans

Systems Group, Dermatology, University of Edinburgh, Edinburgh, United Kingdom.
The American Journal of Human Genetics (Impact Factor: 10.99). 11/2004; 75(5):739-51. DOI: 10.1086/425285
Source: PubMed

ABSTRACT Humans vary >100-fold in their sensitivity to the harmful effects of ultraviolet radiation. The main determinants of sensitivity are melanin pigmentation and less-well-characterized differences in skin inflammation and repair processes. Pigmentation has a high heritability, but susceptibility to cancers of the skin, a key marker of sun sensitivity, is less heritable. Despite a large number of murine coat-color mutations, only one gene in humans, the melanocortin 1 receptor (MC1R), is known to account for substantial variation in skin and hair color and in skin cancer incidence. MC1R encodes a 317-amino acid G-coupled receptor that controls the relative amounts of the two major melanin classes, eumelanin and pheomelanin. Most persons with red hair are homozygous for alleles of the MC1R gene that show varying degrees of diminished function. More than 65 human MC1R alleles with nonsynonymous changes have been identified, and current evidence suggests that many of them vary in their physiological activity, such that a graded series of responses can be achieved on the basis of (i) dosage effects (of one or two alleles) and (ii) individual differences in the pharmacological profile in response to ligand. Thus, a single locus, identified within a Mendelian framework, can contribute significantly to human pigmentary variation.

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    • "Skin pigmentation is strikingly diverse in humans, varying from very dark to very light with increasing distance from the equator (Jablonski and Chaplin 2000). This is likely a result of intense positive selection achieving a balance between UV protection (Armstrong et al. 1997; Palmer et al. 2000; Rees 2004) on one hand and vitamin D synthesis (Branda and Eaton 1978) on the other. Furthermore, it has been suggested that sexual selection via mate choice preference played a role in the diversity of human skin coloration around the world (Aoki 2002). "
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    ABSTRACT: Natural variation in human skin pigmentation is primarily due to genetic causes rooted in recent evolutionary history. Genetic variants associated with human skin pigmentation confer risk of skin cancer and may provide useful information in forensic investigations. Almost all previous gene-mapping studies of human skin pigmentation were based on categorical skin color information known to oversimplify the continuous nature of human skin coloration. We digitally quantified skin color into hue and saturation dimensions for 5,860 Dutch Europeans based on high-resolution skin photographs. We then tested an extensive list of 14,185 single nucleotide polymorphisms in 281 candidate genes potentially involved in human skin pigmentation for association with quantitative skin color phenotypes. Confirmatory association was revealed for several known skin color genes including HERC2, MC1R, IRF4, TYR, OCA2, and ASIP. We identified two new skin color genes: genetic variants in UGT1A were significantly associated with hue and variants in BNC2 were significantly associated with saturation. Overall, digital quantification of human skin color allowed detecting new skin color genes. The variants identified in this study may also contribute to the risk of skin cancer. Our findings are also important for predicting skin color in forensic investigations.
    Human Genetics 10/2012; 132(2). DOI:10.1007/s00439-012-1232-9 · 4.52 Impact Factor
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    • "The human MC1R gene is highly polymorphic (Garcia-Borron et al., 2005) and several variants, such as the Arg 151 Cys (R 151 C) mutation, result in loss of function of MC1R (Ringholm et al., 2004) and are associated with the red hair color phenotype (RHC) (Valverde et al., 1995; Box et al., 1997; Healy et al., 2000; Rees, 2004), poor tanning ability, and elevated risk of melanoma and carcinoma (Palmer et al., 2000; Kennedy et al., 2001; Sturm et al., 2003; Soufir et al., 2009). These variants can bind to a-MSH but are unable to activate adenylate cyclase in cultured cells (Healy et al., 2001; Ringholm et al., 2004; Newton et al., 2005, 2007; Sanchez-Laorden et al., 2007; Herraiz et al., 2009). "
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    ABSTRACT: Ultraviolet A (UVA) radiations are responsible for deleterious effects, mainly due to reactive oxygen species (ROS) production. Alpha-melanocyte stimulating hormone (α-MSH) binds to melanocortin-1 receptor (MC1R) in melanocytes to stimulate pigmentation and modulate cutaneous inflammatory responses. MC1R may be induced in keratinocytes after UV exposure. To investigate the effect of MC1R signaling on UVA-induced ROS (UVA-ROS) production, we generated HaCaT cells that stably express human MC1R (HaCaT-MC1R) or the Arg151Cys (R(151)C) non-functional variant (HaCaT-R(151)C). We then assessed ROS production immediately after UVA exposure and found that: (1) UVA-ROS production was strongly reduced in HaCaT-MC1R but not in HaCaT-R(151)C cells compared to parental HaCaT cells; (2) this inhibitory effect was further amplified by incubation of HaCaT-MC1R cells with α-MSH before UVA exposure; (3) protein kinase A (PKA)-dependent NoxA1 phosphorylation was increased in HaCaT-MC1R compared to HaCaT and HaCaT-R(151)C cells. Inhibition of PKA in HaCaT-MC1R cells resulted in a marked increase of ROS production after UVA irradiation; (4) the ability of HaCaT-MC1R cells to produce UVA-ROS was restored by inhibiting epidermal growth factor receptor (EGFR) or extracellular signal-regulated kinases (ERK) activity before UVA exposure. Our findings suggest that constitutive activity of MC1R in keratinocytes may reduce UVA-induced oxidative stress via EGFR and cAMP-dependent mechanisms.
    Journal of Cellular Physiology 06/2012; 227(6):2578-85. DOI:10.1002/jcp.22996 · 3.87 Impact Factor
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    • "The skin sensitivity to the effects of ultraviolet radiation (UVR) is variable within the normal population, and skin exposure to a significant dose of UVR leads to an inflammatory reaction characterized by erythema (redness), oedema and possibly pain and blistering (sunburn). Although associations between TP53 codon 72 polymorphism and various types of cancer, including skin cancer, were registered (Hsieh and Lin 2006), a few allelic association studies between candidate genes and experimentally induced UVR erythema have been reported (Rees 2004; Benjamin et al. 2008; Han et al. 2008). The purpose of this study was to establish a possible association between polymorphism at codon 72 of TP53 gene and pigmentation features such as skin, hair and eye colour as well as skin reactions (redness or tanning) after exposure to sunlight. "
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    ABSTRACT: The p53 protein exerts different cellular functions, and recent findings have demonstrated its influence on the cascade of skin pigmentation during UV exposure. Among TP53 gene polymorphisms, the most studied is the G to C transversion in exon 4 at codon 72, which results in three distinct genotypes, Arg/Arg, Pro/Pro and Arg/Pro, each one encoding different p53 isoforms. Therefore, this study aimed to determine the relationship between TP53 codon 72 polymorphism and skin protection against sunburn. Genomic DNA was extracted from peripheral blood samples and genotyping was performed by PCR and confirmed by restriction enzyme digestion. The genotype frequency was 50% for Arg/Arg and 14.6% for Pro/Pro genotype. The frequency of heterozygous subjects was 35.4%. In our population, p53 genotypes were in Hardy-Weinberg (HW) equilibrium (X2 HM less than 3.84), showing a predominance of arginine allele (total Arg allele frequency of 68%). No significant association between p53 genotype and skin colour, hair or eye colour and susceptibility to sun exposure was found. However, further analysis demonstrated a significant association between the genotype Pro/Pro and blue/green eyes among participants who presented redness (P=0.016). Our findings indicate susceptibility to sun exposure when this phenotype (eye colour) occurs simultaneously with Pro/Pro genotype.
    Journal of Biosciences 03/2012; 37(1):33-9. DOI:10.1007/s12038-012-9183-9 · 1.94 Impact Factor
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