Human Molecular Genetics, 2001, Vol. 10, No. 16 1701-1708
© 2001 Oxford University Press
The melanocortin-1-receptor gene is the major freckle gene
Department of Dermatology and 1Department of Clinical Epidemiology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands
Received April 17, 2001; Revised and Accepted June 12, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Ephelides and solar lentigines are different types of pigmented skin lesions. Ephelides appear early in childhood and are associated with fair skin type and red hair. Solar lentigines appear with increasing age and are a sign of photodamage. Both lesions are strong risk indicators for melanoma and non-melanoma skin cancer. Melanocortin-1-receptor (MC1R) gene variants are also associated with fair skin, red hair and melanoma and non-melanoma skin cancer. The purpose of this study was to investigate the relationship between MC1R gene variants, ephelides and solar lentigines. In a large case-control study, patients with melanoma and non-melanoma skin cancer and subjects without a history of skin cancer were studied. In all participants, the presence of ephelides in childhood and solar lentigines by physical examination was assessed according to strict definitions. The entire coding sequence of the MC1R gene was analyzed by single-strand conformation polymorphism analysis followed by sequence analyses. Carriers of one or two MC1R gene variants had a 3- and 11-fold increased risk of developing ephelides, respectively (both P < 0.0001), whereas the risk of developing severe solar lentigines was increased 1.5- and 2-fold (P = 0.035 and P < 0.0001), respectively. These associations were independent of skin type and hair color, and were comparable in patients with and without a history of skin cancer. The population attributable risk for ephelides to MC1R gene variants was 60%, i.e. 60% of the ephelides in the population was caused by MC1R gene variants. A dosage effect was found between the degree of ephelides and the number of MC1R gene variants. As nearly all individuals with ephelides were carriers of at least one MC1R gene variant, our data suggest that MC1R gene variants are necessary to develop ephelides. The results of the study also suggest that MC1R gene variants play a role, although less important, in the development of solar lentigines.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Ephelides are small pigmented spots of the skin commonly occuring in the Caucasian population, more frequently in fair-skinned individuals with red or light-blond hair (1). The spots are best visible after sun exposure and in summer. Ephelides appear early in childhood and partly vanish with age. Fair skin, red hair and ephelides are indicators for an increased risk of malignant melanoma and non-melanoma skin cancer (2–4). Ephelides must be distinguished from solar lentigines which occur more frequently with increasing age and can be considered as a sign of photodamage (5).
The melanocortin-1-receptor (MC1R) gene plays an important role in the genetics of human pigmentation (6–8). Stimulation of MC1R by 
-melanocyte-stimulating hormone (-MSH) and other pro-opiomelanocortin (POMC) peptides lead to enhanced adenylate cyclase and cAMP resulting in synthesis of the black photoprotective eumelanin pigment instead of the red phaeomelanin (9). Phaeomelanin which may contribute to skin carcinogenesis by producing free radicals in response to ultraviolet radiation (10) is predominantly present in individuals with red hair and fair skin, which may explain the sun sensitivity and inability to tan of these individuals (11). The human MC1R gene, localized on chromosome 16q24.3 (12,13), is highly polymorphic in the white population (14) and MC1R gene variants have been found to be associated with fair skin and red hair (15–19). Moreover, MC1R gene variants are associated with an increased risk of cutaneous malignant melanoma (20–22) and non-melanoma skin cancer (17,19).
Two studies have investigated the association between MC1R variant alleles and freckling. The first study recorded the number of freckling sites by history up to a maximum of seven sites including the face, shoulders, back and arms (18). The exact meaning of ‘history’, however, was not specified. They found a significant association (P < 0.0001) between MC1R gene variants and the number of freckling sites. The second study recorded levels of UV-induced skin damage indicated, for example, by back freckling (17). Significant associations between any MC1R gene variants and the red hair color variant alleles (Arg151Cys, Arg160Trp and Asp294His) were found. Although the freckling was not specified, the first study probably investigated ephelides and the second study solar lentigines.
The close relationship between red hair, fair skin and ephelides also prompted us to investigate the association between MC1R gene variants and ephelides. Because solar lentigines must be differentiated from ephelides, we also studied the association between MC1R gene variants and solar lentigines and compared this association with the former one.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Composition of study population
The general characteristics of the study group were described by De Hertog et al. (23). In short, 1019 participants were interviewed and examined at the Dermatology out-patient clinic of the Leiden University Medical Centre. Of the subjects who attended the study, 57 were excluded because they did not fulfill the inclusion criteria. Among these, in four individuals MC1R genotyping was not successful because no DNA or PCR product could be obtained. The final series for analysis comprised 962 subjects: 124 subjects with melanoma, 161 subjects with squamous cell carcinoma, 300 with nodular basal cell carcinoma, 151 with superficial multifocal basal cell carcinoma and 385 participants without a history of skin cancer. A total of 140 subjects had more than one type of skin cancer (23).
Characteristics of subjects with ephelides and solar lentigines
The characteristics of the subjects with ephelides in childhood, ephelides by physical examination and solar lentigines by physical examination are shown in Table 1. Of all 962 participants, 378 (39.3%) had ephelides in childhood. Ephelides in childhood and by physical examination were significantly more common among all cancer groups as compared to the control subjects (P < 0.05), although the association between ephelides by physical examination and skin cancer was less strong. Of the 962 subjects, 879 (91.4%) had solar lentigines by physical examination and 474 (49.3%) had severe solar lentigines. Solar lentigines were significantly more common among patients with non-melanoma skin cancers. These data illustrate the relationship between ephelides and solar lentigines and skin cancer.
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Of all 378 participants with ephelides in childhood, 192 (50.8%) had ephelides by physical examination. Of the 519 participants who had no history of ephelides in childhood, 61 (10.6%) showed ephelides by physical examination.
Association between the most common MC1R gene variants and ephelides and solar lentigines
Of the 27 MC1R gene variants which were found, the nine most common were Val60Leu, Asp84Glu, Val92Met, Arg142His, Arg151Cys, Arg160Trp, Arg163Gln, His260Pro and Asp294His (19). Eighteen variants showed a frequency <0.5% of total alleles. Of the total study population, 261 (27.1%) subjects had no MC1R gene variants, 440 (45.7%) had one MC1R gene variant, 251 (26.1%) had two MC1R gene variants and 10 (1.1%) had three MC1R gene variants. The group with more than one variant allele comprised 37 homozygotes and 224 compound heterozygotes i.e. two different variant alleles. Of the 1924 alleles, only 11 showed two variants within the same allele which occurred in 11 different individuals. Ten of these individuals also showed a variant in the other allele, and in one individual the other allele was wild-type.
The combinations of alleles of all participants and the frequency of these combinations in subjects with red hair, ephelides in childhood and severe solar lentigines, respectively, are shown in Table 2. The genotype data indicate that the MC1R gene variants Arg151Cys, Arg160Trp and Asp294His homozygotes and heterozygotes contribute most to the prevalence of red hair and ephelides in childhood. The genotype table also suggests that all other common variants act as recessive alleles for ephelides in childhood in various combinations with other alleles.
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The risks of ephelides in childhood and severe solar lentigines in carriers of one common MC1R gene variant (heterozygotes) and combined with another variant allele (compound heterozygotes and homozygotes) are shown in Table 3. All common MC1R gene variants were strongly associated with ephelides in childhood. Asp294His in combination with another MC1R gene variant showed the highest risk of ephelides followed by His260Pro, Arg142His and Arg151Cys in combination with another variant allele. Because of small numbers, however, 95% confidence intervals (95% CI) are wide. The MC1R gene variants were also associated with solar lentigines, though less strongly. Asp294His, Asp84Glu and His260Pro showed the highest association with solar lentigines.
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The population attributable risk for ephelides to MC1R gene variants was 60%, which indicates that 60% of the ephelides in the population was caused by MC1R gene variants.
Associations between ephelides by physical examination and MC1R gene variants were similar although somewhat weaker compared to the associations between ephelides in childhood and MC1R gene variants (data not shown).
Ephelides are strongly associated with MC1R gene variants independent of skin type and hair color
Ephelides in childhood were highly associated with the presence of one [odds ratio (OR) 3.1, 95% CI 2.1–4.6] and two (OR 10.8, 95% CI 7.0–16.9) MC1R gene variants (Table 4). The association was present in all skin types. The pooled OR adjusted for skin type using the Mantel–Haenszel test was only slightly lower than the crude OR, indicating that MC1R gene variants are strongly associated with ephelides in childhood independent of skin type. Similar results were also found for the different hair colors (data not shown).
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The presence of one or two MC1R gene variants was also significantly associated with solar lentigines, although the risks were significantly lower compared to ephelides (OR 1.6, 95% CI 1.2–2.2; OR 2.2, 95% CI 1.5–3.1, respectively). The association was slightly lower in subjects with darker skin types (Table 4). Stratification into subjects with different hair colors revealed similar results (data not shown).
Analyses in the different subgroups consisting of subjects with melanoma and non-melanoma skin cancer, and subjects without a history of skin cancer, showed similar results compared to the analyses in the total group (data not shown).
Degree of freckling is associated with presence of MC1R gene variants
A significant association was found between the degree of ephelides in childhood and the presence of MC1R gene variants (P < 0.0001) (Fig. 1). This association showed a clear dosage effect: the degree of freckling was positively related to the number of MC1R gene variants. A significant dosage effect was also seen between the degree of solar lentigines and MC1R gene variants (P < 0.0001) (Fig. 1); however, the number of subjects with higher degrees of solar lentigines and no variant MC1R gene alleles was considerable.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Ephelides in childhood were strongly associated with the presence of MC1R gene variants independent of skin type and hair color. Only 42 of the 378 subjects with ephelides had no MC1R gene variants. Also, the degree of ephelides was associated with the number of MC1R gene variants. Both ephelides and MC1R gene variants are common in the Dutch population. The high prevalence of MC1R gene variants and ephelides and the strong association between these variables indicate that the MC1R gene contributes largely to the etiology of ephelides and suggests the MC1R gene to be the major ephelides gene. The population attributable risk for ephelides to MC1R gene variants was 60%, i.e. 60% of the ephelides in the population was caused by MC1R gene variants. However, expression of the gene is not complete as half of the carriers do not have ephelides. Smaller but still statistically significant associations were also found between MC1R gene variants and solar lentigines. Thus, the MC1R gene also plays a role in the development of solar lentigines.
MC1R gene variants are strongly associated with red hair and a poor tanning response (15,18) and according to our study determine the presence of ephelides. This suggests that in humans the MC1 receptor is a key regulator of pigmentation phenotype and sun sensitivity. Melanocytes, which are stimulated by -MSH through the MC1R, synthesize the black photoprotective eumelanin pigment instead of red phaeomelanin (9). Individuals with red hair and fair skin predominantly synthesize phaeomelanin (11). In mice, MC1R gene variants leading to loss of function of the receptor result in an overproduction of phaeomelanin and consequently yellow hair (24). In this light, it would be interesting to know the relative proportions of eumelanine and phaeomelanine in ephelides. The histology of ephelides is characterized by hyperpigmentation of the epidermis, usually with a decrease in the number of melanocytes (25); however, information of the eumelanine/phaeomelanine ratio has been lacking until now.
Some of the MC1R gene variants, Val60Leu, Arg142His, Arg151Cys, Arg160Trp and Asp294His, have been found to be unable to stimulate cAMP production as strongly as the wild-type receptor in response to -MSH stimulation and may therefore alter the function of the receptor (26,27). Of these variants, Asp294His, Arg142His, Arg151Cys and Arg160Trp revealed the highest associations with ephelides in our study. His260Pro was also associated with ephelides. A reduced binding affinity of this variant allele for -MSH was found (28). Therefore, MC1R gene variants encoding proteins with altered receptor binding and/or signalling properties seem to be most important in determining the risk of ephelides.
Solar lentigines are considered a sign of photodamage, although genetic factors also play a role. Solar lentigines were found to be associated with MC1R gene variants in our study. Ultraviolet light was found to induce the release of -MSH and other POMC peptides and to upregulate the expression of the MC1 receptor in the epidermis (29,30). Therefore, it has been suggested that -MSH may play a role in regulating responses to UV radiation. -MSH may also play a role in proliferation and differentiation of melanocytes and keratinocytes (31–35), and in immune processes and inflammation (7,36). Because solar lentigines are histologically characterized by epidermal hyperplasia with functionally active melanocytes (37), these proliferation and differentiation mechanisms may be important in explaining the association between MC1R gene variants and solar lentigines.
The clinical differentiation between ephelides and solar lentigines on the basis of morphological features can be difficult. Solar lentigines may already appear in childhood (38). Assessing ephelides in childhood by history may harbor the risk of misclassification. This form of misclassification, however, would have only weakened the associations found in our study. Moreover, the results of our study show that the approach we used for defining and assessing ephelides and solar lentigines was useful in discriminating these two pigmented spots.
The findings in this study once more indicate that ephelides and solar lentigines are different types of pigmented lesions and clearly show differences in their etiology. MC1R gene variants are a necessary factor to develop ephelides, whereas they play a less critical role in the etiology of solar lentigines.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Study population
The Leiden skin cancer study (LSS) is an extensive hospital-based case-control study which started in 1997 and in which environmental and genetic risk factors for different types of skin cancer are studied in the Dutch population. The design of the study has been described before (23). Shortly, the study population consisted of subjects aged 30–80 years with histologically proven squamous cell carcinoma, nodular and superficial multifocal basal cell carcinoma, malignant melanoma and controls. Participants without a history of skin cancer were selected from the Ophthalmology out-patient clinic of the Leiden University Medical Center. Only individuals with skin types I–IV according to the classification of Fitzpatrick (39) were included.
Assessment of ephelides and solar lentigines
Ephelides are considered as the combined outcome of pigmentary traits, sun sensitivity and sun exposure. They appear early in childhood and partly vanish with age. Therefore, in studies investigating risk factors for skin cancer, ephelides are usually assessed by history for the childhood period (4,40,41). Recording ephelides at adult age either by subjects’ own assessment or at physical examination by a dermatologist may harbor the risk of misclassification with solar lentigines (1). In the present study, participants were asked if they had ephelides in childhood (
15 years of age) localized in the face, on the arms or upper back. Ephelides were defined as multiple, small (1–3 mm), pale-brown macular lesions with a poorly defined margin which are more pronounced in summer. This was illustrated with use of a chart which was originally proposed for classification of melanocytic nevi by Gallagher et al. (42), and was thereafter named as a ‘freckling chart’ in the Geraldton Skin Cancer Prevention Survey by Kricker et al. (43). The participants were asked to rate the severity of their childhood freckling for each location using a scale from 0 (no childhood freckling) to 5 (very severe childhood freckling). The total score was determined in terms of the sum of the three locations (minimum 0, maximum 15). Eight subjects were not able to recall the presence or absence of ephelides in childhood and were not included in the analyses. Ephelides were also assessed by physical examination by a dermatologist using a standard protocol. Using the freckling chart, the severity of ephelides by physical examination was rated.
Solar lentigines are mainly considered as an indicator of sun damage although genetic background plays an additional role. They can best be recorded by a dermatologist investigating anatomic skin sites which are chronically exposed to the sun, such as the face, the neck, the fore-arms and hands (4,41). We recorded solar lentigines examining the face, the arms and upper back. This was performed by a dermatologist using a standard protocol. Solar lentigines were defined as round to polycyclic, brown to black–brown, macular or slightly raised lesions up to 1 cm in diameter with a sparse and scattered distribution (1). Using the freckling chart, the severity of solar lentigines was rated for each location using a scale from 0 (no solar lentigines) to 5 (very severe lentigines). The total score was determined in terms of the sum of the three locations (minimum 0, maximum 15). In two subjects, information on the presence of solar lentigines was not available and these subjects were not included in the analyses.
Assessment of skin type and hair color
In assessing skin type, the subjects’ own assessments of their propensity to sunburn and ability to tan were ascertained at interview. Skin type was recorded according to the classification of Fitzpatrick (39) as follows: always burn, never tan (skin type I), always burn, then tan (skin type II), always tan, sometimes burn (skin type III) and always tan, never burn (skin type IV). Original or natural hair color was also ascertained by history at 20 years of age and classified into five categories: red, light blond, dark blond, brown or black.
Detection of MC1R gene variants
Genomic DNA was isolated from peripheral blood leukocytes of all participants by routine methods (44). The MC1R gene coding sequence (GenBank accession no. X65634) was amplified by PCR in the following reaction: 200 ng genomic template DNA, 60 mM Tris–HCl pH 10.0, 2.0 mM MgCl2, 15 mM (NH4)2SO4, 100 µM each dGTP, dTTP, dATP and dCTP, 1 µl [-32P]dCTP (3000 Ci/mmol), 500 ng of each PCR primer, 2 U AmpliTaq (Perkin Elmer-Cetus) and 10% DMSO in a total volume of 100 µl. Samples were covered with mineral oil, denatured for 4 min at 92°C, and passed through 33 cycles of amplification, consisting of 50 s denaturation at 92°C, 50 s primer annealing at 58°C, 2 min elongation at 72°C. The amplifications were carried out in 0.5 ml tubes (Perkin Elmer). The DNA sequences of the primers were: F-5'-CAACGACT-CCTTCCTGCTTC-3' and R-5'-TGCCCAGCACACTTAAAGC-3'. The resulting 1018 bp PCR fragment was digested by 2 U of either RsaI or MspI, and screened for mutations by single-strand conformation polymorphism analysis (45) on a 6% polyacrylamide gel with 10% glycerol. The gels were run at room temperature for 6 h at 28 W or 16 h at 20 W for MspI and RsaI digests, respectively.
Sequence analysis
DNA samples for sequencing were obtained by PCR as described above with M13-tailed MC1R gene primers M13MC1R-F-5'-TGTAAAACGACGGCCAGTCAACGACTCCTTCCTGCTTC-3' and M13MC1R-IR-5'-CAGGAAACAGCTATGACCATGAGTCACGATGCTGTGGTAGC-3', resulting in a 542 bp fragment, and the primers M13MC1R-IF-5'-GACGTTGTAAACGACGGCCAGTACCTGCAGCTCCATGCTGTC-3' and M13MC1R-R-5'-CAGGAAACAGCTATGACCATGATGCCCAGCACACTTAAAGC-3', resulting in a 661 bp fragment. Sequence analysis was performed on an ABI-377 automated DNA sequencer using Big-Dye Terminator Cycle Sequencing kits (Perkin Elmer) according to the manufacturer’s instructions.
Statistical analyses and strategy of analyses
Ephelides in childhood and by physical examination and solar lentigines by physical examination were firstly classified in three categories: absent (score 0), non-severe (score 1–3) and severe (score 4–15). In the analyses with MC1R gene variants, ephelides were dichotomised into absent and present (non-severe and severe together). Because of the high prevalence of solar lentigines, in the analyses with MC1R gene variants these spots were dichotomised into non-severe (absent and non-severe together) and severe. In some analyses with MC1R gene variants, only ephelides in childhood were used because this was considered as the most accurate method of assessing these spots. To investigate a dosage effect between the degree of ephelides and solar lentigines and MC1R gene variants, the total scores of ephelides in childhood and solar lentigines were divided into eight categories: 0 (absent), 1–6 (scores 1 to 6) and 7 (score 7 or more).
2 analysis was used to compare the prevalence of ephelides and solar lentigines in controls and in the different patient groups. Exposure ORs with 95% CIs were calculated to estimate the relative risk for the presence of ephelides and the severity of solar lentigines dependent on the MC1R gene variants. Analyses between MC1R gene variants and ephelides and solar lentigines were firstly performed with the nine most common MC1R gene variants, separately, and secondly with all MC1R gene variants together.
In the analyses, skin type and hair color were considered possible confounding factors and the association between all MC1R gene variants and ephelides and solar lentigines were therefore also analyzed in strata of skin type (skin types I/II and III/IV) and hair color (red and non-red). All analyses were performed in the total study group, and also in the patient groups and in controls, separately. The population attributable risk for ephelides to MC1R gene variants was calculated.
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ACKNOWLEDGEMENTS |
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We would like to thank all patients and controls, and all members of the LSS for voluntarily and enthusiastically participating in this study. The work was supported by a grant from Zorg Onderzoek Nederland (ZON).
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +31 71 5262421; Fax: +31 71 5248106; Email: j.n.bouwes_bavinck@lumc.nl
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REFERENCES |
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