Melanocortin-1 Receptor Genotype is a Risk Factor for Basal and Squamous Cell Carcinoma
2001; Elsevier BV; Volume: 116; Issue: 2 Linguagem: Inglês
10.1046/j.1523-1747.2001.01224.x
ISSN1523-1747
AutoresNeil F. Box, Wei Chen, Richard A. Sturm, David L. Duffy, Rachel E. Irving, Anne Russell, Lyn R. Griffyths, Peter G. Parsons, Adèle C. Green,
Tópico(s)Dermatologic Treatments and Research
ResumoMC1R gene variants have previously been associated with red hair and fair skin color, moreover skin ultraviolet sensitivity and a strong association with melanoma has been demonstrated for three variant alleles that are active in influencing pigmentation: Arg151Cys, Arg160Trp, and Asp294His. This study has confirmed these pigmentary associations with MC1R genotype in a collection of 220 individuals drawn from the Nambour community in Queensland, Australia, 111 of whom were at high risk and 109 at low risk of basal cell carcinoma and squamous cell carcinoma. Comparative allele frequencies for nine MC1R variants that have been reported in the Caucasian population were determined for these two groups, and an association between prevalence of basal cell carcinoma, squamous cell carcinoma, solar keratosis and the same three active MC1R variant alleles was demonstrated [odds ratio = 3.15 95% CI (1.7, 5.82)]. Three other commonly occurring variant alleles: Val60Leu, Val92Met, and Arg163Gln were identified as having a minimal impact on pigmentation phenotype as well as basal cell carcinoma and squamous cell carcinoma risk. A significant heterozygote effect was demonstrated where individuals carrying a single MC1R variant allele were more likely to have fair and sun sensitive skin as well as carriage of a solar lesion when compared with those individuals with a consensus MC1R genotype. After adjusting for the effects of pigmentation on the association between MC1R variant alleles and basal cell carcinoma and squamous cell carcinoma risk, the association persisted, confirming that presence of at least one variant allele remains informative in terms of predicting risk for developing a solar-induced skin lesion beyond that information wained through observation of pigmentation phenotype. MC1R gene variants have previously been associated with red hair and fair skin color, moreover skin ultraviolet sensitivity and a strong association with melanoma has been demonstrated for three variant alleles that are active in influencing pigmentation: Arg151Cys, Arg160Trp, and Asp294His. This study has confirmed these pigmentary associations with MC1R genotype in a collection of 220 individuals drawn from the Nambour community in Queensland, Australia, 111 of whom were at high risk and 109 at low risk of basal cell carcinoma and squamous cell carcinoma. Comparative allele frequencies for nine MC1R variants that have been reported in the Caucasian population were determined for these two groups, and an association between prevalence of basal cell carcinoma, squamous cell carcinoma, solar keratosis and the same three active MC1R variant alleles was demonstrated [odds ratio = 3.15 95% CI (1.7, 5.82)]. Three other commonly occurring variant alleles: Val60Leu, Val92Met, and Arg163Gln were identified as having a minimal impact on pigmentation phenotype as well as basal cell carcinoma and squamous cell carcinoma risk. A significant heterozygote effect was demonstrated where individuals carrying a single MC1R variant allele were more likely to have fair and sun sensitive skin as well as carriage of a solar lesion when compared with those individuals with a consensus MC1R genotype. After adjusting for the effects of pigmentation on the association between MC1R variant alleles and basal cell carcinoma and squamous cell carcinoma risk, the association persisted, confirming that presence of at least one variant allele remains informative in terms of predicting risk for developing a solar-induced skin lesion beyond that information wained through observation of pigmentation phenotype. basal cell carcinoma melanocortin-1 receptor nonmelanocytic skin cancer red hair color solar keratosis The major environmental causative factor for basal and squamous cell carcinomas (BCC and SCC) is solar ultraviolet (UV) irradiation, which is important both in terms of total cumulative lifetime exposure and in terms of exposure profiles for these two types of tumors (IARC, 1992IARC Monograph. Solar and ultraviolet radiation.in: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 55. International Agency for Research on Cancer, Lyon1992Google Scholar;Rosso et al., 1996Rosso S. Zanetti R. Martinez C. et al.The multicentre south European study ''Helios''. II. Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin.Br J Cancer. 1996; 73: 1447-1454Crossref PubMed Scopus (319) Google Scholar;English et al., 1998bEnglish D.R. Armstrong B.K. Kricker A. Winter M.G. Heenan P.J. Randell P.L. Case-control study of sun exposure and squamous cell carcinoma of the skin.Int J Cancer. 1998; 77: 347-353Crossref PubMed Scopus (107) Google Scholar). It has been speculated that tumorigenic transformation of epithelial cells requires significantly less UV for BCC than for SCC and where tanning ov the skin is able to develop and exposure continues, subjects tend to develop SCC rather than BCC (Rosso et al., 1996Rosso S. Zanetti R. Martinez C. et al.The multicentre south European study ''Helios''. II. Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin.Br J Cancer. 1996; 73: 1447-1454Crossref PubMed Scopus (319) Google Scholar). UV may only be one factor for BCC, other influences may include diet (Wei et al., 1994Wei Q. Matanoski G.M. Farmer E.R. Strickland P. Grossman L. Vitamin supplementation and reduced risk of basal cell carcinoma.J Clin Epidemiol. 1994; 47: 829-836Abstract Full Text PDF PubMed Scopus (23) Google Scholar) and the basal rate of tumors. Solar keratoses (SK) are premalignant UV-induced skin lesions that rarely transform to become SCC, but which often spontaneously regress (Frost et al., 2000Frost C. Williams G. Green A. High incidence and regression rates of solar keratoses in a Queensland community.J Invest Dermatol. 2000; 115: 273-277https://doi.org/10.1046/j.1523-1747.2000.00048.xCrossref PubMed Scopus (143) Google Scholar). Presence of an SK in individuals strongly predicts their potential to develop both BCC and SCC and is regarded as an indicator of excessive sun exposure (Marks et al., 1988Marks R. Rennie G. Selwood T. The relationship of basal cell carcinomas and squamous cell carcinomas to solar keratoses.Arch Dermatol. 1988; 124: 1039-1042Crossref PubMed Scopus (130) Google Scholar;Marks, 1990Marks R. Solar keratoses.Br J Dermatol. 1990; 122: 49-54Crossref PubMed Scopus (46) Google Scholar). Constitutional factors also determine an individual's potential to develop BCC and SCC, with the skin's reaction to sunlight or ''skin type'' an important determinant of skin cancer risk. Although other factors such as skin thickness or DNA repair ability may influence the skin response to UV and, therefore, risk of skin cancer, pigmentation is clearly a central element in the interaction of the skin with UV light. Pigmentary traits such as fair skin, lack of tanning ability, and propensity to freckle have been identified as risk factors (Green and Battistutta, 1990Green A. Battistutta D. Incidence and determinants of skin cancer in a high-risk Australian population.Int J Cancer. 1990; 46: 356-361Crossref PubMed Scopus (200) Google Scholar;Kricker et al., 1991Kricker A. Armstrong B.K. English D.R. Heenan P.J. Pigmentary and cutaneous risk factors for non-melanocytic skin cancer a case-control study.Int J Cancer. 1991; 48: 650-662Crossref PubMed Scopus (204) Google Scholar;Green et al., 1996Green A. Battistutta D. Hart V. Leslie D. Weedon D. Skin cancer in a subtropical Australian population: incidence and lack of association with occupation. The Nambour Study Group.Am J Epidemiol. 1996; 144: 1034-1040Crossref PubMed Scopus (199) Google Scholar;Zanetti et al., 1996Zanetti R. Rosso S. Martinez C. et al.The multicentre south European study ''Helios''. 1: Skin characteristics and sunburns in basal cell and squamous cell carcinomas of the skin.Br J Cancer. 1996; 73: 1440-1446Crossref PubMed Scopus (160) Google Scholar;English et al., 1998aEnglish D.R. Armstrong B.K. Kricker A. Winter M.G. Heenan P.J. Randell P.L. Demographic characteristics, pigmentary and cutaneous risk factors for squamous cell carcinoma of the skin: a case-control study.Int J Cancer. 1998; 76: 628-634Crossref PubMed Scopus (116) Google Scholar). The associations between light eye color and red or fair hair observed in these studies indicate that these traits are probably risk indicators by virtue of an interrelationship with a poor skin response to UV. Given that pigmentation influences nonmelanocytic skin cancer (NMSC) risk, the identification of gene variants at the melanocortin 1 receptor (MC1R), which control the production of red pigmentation in Caucasian individuals, suggests that allelic variation within this gene should likewise be associated with skin cancer risk (Valverde et al., 1995Valverde P. Healy E. Jackson I. Rees J.L. Thody A.J. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans.Nature Genet. 1995; 11: 328-330Crossref PubMed Scopus (796) Google Scholar;Box et al., 1997Box N.F. Wyeth J.R. O'Gorman L.E. Martin N.G. Sturm R.A. Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair.Hum Mol Genet. 1997; 6: 1891-1897https://doi.org/10.1093/hmg/6.11.1891Crossref PubMed Scopus (292) Google Scholar;Smith et al., 1998Smith R. Healy E. Siddiqui S. et al.Melanocortin 1 receptor variants in an Irish population.J Invest Dermatol. 1998; 111: 119-122https://doi.org/10.1046/j.1523-1747.1998.00252.xCrossref PubMed Scopus (215) Google Scholar;Sturm et al., 1998Sturm R.A. Box N.F. Ramsay M. Human pigmentation genetics: the difference is only skin deep.Bioessays. 1998; 20: 712-721Crossref PubMed Scopus (150) Google Scholar). MC1R is a seven-pass transmembrane G-protein coupled receptor expressed by skin melanocytes that activates adenylate cyclase to elevate cyclic adenosine monophosphate levels upon stimulation by the proopiomelanocortin-derived peptides α-melanocyte-stimulating hormone and adrenocorticotropic hormone (Thody and Graham, 1998Thody A.J. Graham A. Does alpha-MSH have a role in regulating skin pigmentation in humans?.Pigment Cell Res. 1998; 11: 265-274Crossref PubMed Scopus (92) Google Scholar). Hormonal stimulation of MC1R leads to eumelanogenesis and is central to the tanning response of human melanocytes following UV irradiation (Suzuki et al., 1999Suzuki I. Im S. Tada A. et al.Participation of the melanocortin-1 receptor in the UV control of pigmentation.J Invest Dermatol Symp Proceedings of The. 1999; 4: 29-34Abstract Full Text PDF PubMed Scopus (51) Google Scholar). It has already been shown that three common MC1R variant alleles, Arg151Cys, Arg160Trp, and Asp294His are associated with an increased incidence of UV-induced melanoma within a large population of south-east Queensland cases and controls, with the conclusion that the effect that MC1R variant alleles have on melanoma is mediated predominantly by an effect on pigmentation phenotype (Palmer et al., 2000Palmer J.S. Duffy D.L. Box N.F. et al.Melanocortin-1 receptor polymorphisms and risk of melanoma: Is the association explained solely by pigmentation phenotype?.Am J Hum Genet. 2000; 66: 176-186https://doi.org/10.1086/302711Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar). At least two studies have attempted to address the issue of MC1R variant allele predisposition to BCC and SCC: the first demonstrated an over-representation of the Asp294His variant in 46 BCC and eight SCC cases vs 25 controls, where Asp294His was the only variant examined (Smith et al., 1998Smith R. Healy E. Siddiqui S. et al.Melanocortin 1 receptor variants in an Irish population.J Invest Dermatol. 1998; 111: 119-122https://doi.org/10.1046/j.1523-1747.1998.00252.xCrossref PubMed Scopus (215) Google Scholar), whereas a second study examining the Asp294His and Val92Met variant alleles in 311 BCC cases and 190 controls failed to observe any association between either of these variants and BCC (Ichii-Jones et al., 1999Ichii-Jones F. Ramachandran S. Lear J. et al.The melanocyte stimulating hormone receptor polymorphism: association of the V92M and A294H alleles with basal cell carcinoma.Clin Chim Acta. 1999; 282: 125-134https://doi.org/10.1016/s0009-8981(99)00017-0Crossref PubMed Scopus (0) Google Scholar). The intention of the our study was to examine the relationship between nine MC1R variants identified in a south-east Queensland community (Box et al., 1997Box N.F. Wyeth J.R. O'Gorman L.E. Martin N.G. Sturm R.A. Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair.Hum Mol Genet. 1997; 6: 1891-1897https://doi.org/10.1093/hmg/6.11.1891Crossref PubMed Scopus (292) Google Scholar) and the prevalence of skin cancer or SK using allele-specific oligonucleotide screening of high-risk and low-risk groups selected from the Nambour Skin Cancer Study (Green et al., 1994Green A. Battistutta D. Hart V. et al.The Nambour Skin Cancer and Actinic Eye Disease Prevention Trial: design and baseline characteristics of participants.Control Clin Trials. 1994; 15: 512-522Abstract Full Text PDF PubMed Scopus (84) Google Scholar,Green et al., 1996Green A. Battistutta D. Hart V. Leslie D. Weedon D. Skin cancer in a subtropical Australian population: incidence and lack of association with occupation. The Nambour Study Group.Am J Epidemiol. 1996; 144: 1034-1040Crossref PubMed Scopus (199) Google Scholar). Data collection for the Nambour skin cancer studies began with an original skin cancer survey in 1986, with subsequent whole-body dermatologic exams conducted in 1992, 1994, and 1996, which recorded numbers of sun-induced lesions in addition to a large selection of other data (Green et al., 1988Green A. Beardmore G. Hart V. Leslie D. Marks R. Staines D. Skin cancer in a Queensland population.J Am Acad Dermatol. 1988; 19: 1045-1052Abstract Full Text PDF PubMed Scopus (169) Google Scholar,Green et al., 1994Green A. Battistutta D. Hart V. et al.The Nambour Skin Cancer and Actinic Eye Disease Prevention Trial: design and baseline characteristics of participants.Control Clin Trials. 1994; 15: 512-522Abstract Full Text PDF PubMed Scopus (84) Google Scholar, Green et al., 1996Green A. Battistutta D. Hart V. Leslie D. Weedon D. Skin cancer in a subtropical Australian population: incidence and lack of association with occupation. The Nambour Study Group.Am J Epidemiol. 1996; 144: 1034-1040Crossref PubMed Scopus (199) Google Scholar, Green et al., 1999Green A. Williams G. Neale R. et al.Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial.Lancet. 1999; 354: 723-729https://doi.org/10.1016/s0140-6736(98)12168-2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar;Green and Battistutta, 1990Green A. Battistutta D. Incidence and determinants of skin cancer in a high-risk Australian population.Int J Cancer. 1990; 46: 356-361Crossref PubMed Scopus (200) Google Scholar). A 10 ml blood sample was also collected and frozen down for the majority of participants in the 1996 skin exam. Of the 1311 participants in the Nambour Study of skin cancer who were observed in the 1996 skin exam, individuals were selected and DNA was extracted (Miller et al., 1988Miller S.A. Dykes D.D. Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells.Nucleic Acids Res. 1988; 16: 1215Crossref PubMed Scopus (17178) Google Scholar) from blood samples obtained from those who were regarded as being the most and least likely to develop BCC or SCC (Lea et al., 1998Lea R.A. Selvey S. Ashton K.J. Curran J.E. Gaffney P.T. Green A.C. Griffiths L.R. The null allele of GSTMI does not affect susceptibility to solar keratoses in the Australian white population.J Am Acad Dermatol. 1998; 38: 631-633Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). The high-risk group was drawn on the basis of presence of at least one clinically confirmed BCC, SCC, or SK, as well as a high level of facial elastosis. An individual only required a single SK to be classed as high risk for developing future solar lesions. Conversely, the low-risk group comprised a subset of individuals from the same study population who were free from any BCC, SCC, or SK and who have had low levels of UV exposure represented by low facial elastosis. Using these groupings a total of 348 individuals were selected, of whom 306 had blood samples collected and frozen during the 1996 exam; however, only 111 individuals from the high-risk group and 109 individuals from the low-risk group were successfully DNA extracted and amplified using the polymerase chain reaction, giving a final study number of 220 individuals. There were no first-degree relatives included in the final selection of 220 individuals. The samples used in this study were drawn primarily with the aid of information collected during or before the 1996 skin exam. Numbers of BCC, SCC and solar keratoses were recorded and levels of UV-induced skin damage indicated by the measures of facial elastosis (none, +, ++, +++) and back freckling (none, +, ++, +++). Subjects were asked to report their hair color at age 21 y (blonde, light brown, red/ginger, auburn, dark brown and black), their skin response to strong sun after a long period without exposure (always burn, never tan; burn then tan; only tan). Natural skin color of nonexposed sites was assessed as a self-report using questionnaires described elsewhere and included the measures fair, medium and olive (Green et al., 1994Green A. Battistutta D. Hart V. et al.The Nambour Skin Cancer and Actinic Eye Disease Prevention Trial: design and baseline characteristics of participants.Control Clin Trials. 1994; 15: 512-522Abstract Full Text PDF PubMed Scopus (84) Google Scholar). Polymerase chain reaction was performed in 96 well plates with the MC1R coding region amplified using 25–50 ng of temFig.DNA, with dot blotting performed as described previously to allow for allele-specific oligonucleotide detection of nine different commonly occurring MC1R variant alleles (Box et al., 1997Box N.F. Wyeth J.R. O'Gorman L.E. Martin N.G. Sturm R.A. Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair.Hum Mol Genet. 1997; 6: 1891-1897https://doi.org/10.1093/hmg/6.11.1891Crossref PubMed Scopus (292) Google Scholar;Palmer et al., 2000Palmer J.S. Duffy D.L. Box N.F. et al.Melanocortin-1 receptor polymorphisms and risk of melanoma: Is the association explained solely by pigmentation phenotype?.Am J Hum Genet. 2000; 66: 176-186https://doi.org/10.1086/302711Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar). Both consensus and variant probes were designed for the Val60Leu, Asp84Glu, Val92Met, Arg142His, Arg151Cys, Ile155Thr, Arg160Trp, Arg163Gln, and Asp294His allele positions. Probes were designed as 15 base allele-specific oligonucleotides with the mismatch centrally positioned to provide maximal binding stability to the complementary sequence and instability of a mismatch. 100 ng of each oligonucleotide were radiolabeled with γ-32P-adenosine triphosphate using polynucleotide kinase (NEB) and fractionated from unincorporated nucleotide by chromatography on Sephadex G-25 (Amersham, Uppsala, Sweden, NAP 5 columns). Identically blotted pairs of filters were prehybridized at 42°C for at least 2 h in the presence of tetramethylammonium chloride (Wood et al., 1985Wood W.I. Gitschier J. Lasky L.A. Lawn R.M. Base composition-independent hybridization in tetramethylammonium chloride: a method for oligonucleotide screening of highly complex gene libraries.Proc Natl Acad Sci USA. 1985; 82: 1585--1588Crossref PubMed Scopus (579) Google Scholar) in 10 ml of 3 M tetramethylammonium chloride, 0.1% sodium dodecyl sulfate, 1 mM ethylenediamine tetraacetic acid, 25 mM Na3PO4 pH 6.8, 5 × Denhardt's solution, 0.1 mg herring sperm DNA per ml (Shuber et al., 1993Shuber A.P. Skoletsky J. Stem R. Handelin B.L. Efficient 12-mutation testing in the CFTR gene: a general model for complex mutation analysis.Hum Mol Genet. 1993; 2: 153-158Crossref PubMed Scopus (82) Google Scholar). Fifty microliters of radiolabeled consensus or variant probe, equating to no less than 2.75 × 105 cpm per ml of hybridization solution, was added directly to the prehybridizing solution of each pair of filters and left to hybridize overnight at 42°C. The probe was denatured by heating to 70°C for 5 min then quenched on ice before addition. Filters were rinsed in 3 M tetramethylammonium chloride, 0.1% sodium dodecyl sulfate, 1 mM ethylenediamine tetraacetic acid, Na3PO4 pH 6.8 wash solution at room temperature for 5 min followed by a single 20 min wash at 50°C before autoradiographic exposure. Under these conditions probes specifically designed to the consensus and variant sequence will detect these sequences alone, but will not remain bound in the heteroduplex form resulting in an ability to specifically detect both consensus and variant alleles. Most analyses were performed using SAS, version 7.0 (SAS Institute, 1998SAS Institute: SAS 7.0. Computer program. SAS Institute, Gary, NC1998Google Scholar), including log-linear and multinomial regression modeling done by means of SAS PROC CATMOD. Pairwise linkage disequilibrium was tested using ASSOCIATE 2.33 (Ott, 1996Ott J. ASSOCIATE 233 Computer Program. Rockefeller University, New York1996Google Scholar) and was quantitated as the standardized pairwise disequilibrium coefficient (D′) (Weir, 1996Weir B.S. Genetic Data Analysis II. Sinauer, New York1996Google Scholar). The presence of a UV-induced lesion was used as the primary criterion for distinguishing between the high- and low-risk groups in this study (Table 1). Individuals in the high-risk group all had a medium level of facial elastosis and a significantly increased level of back freckling (p < 0.0001) when compared with the low-risk group, which had only limited or absent facial elastosis. Both of these are indicators of environmental UV exposure as well as innate sun sensitivity. All of the SCC cases and 93% of BCC cases exhibited concurrent solar keratoses. Furthermore, of the 20 SCC cases, 11 exhibited at least one BCC.Table 1Phenotypic characteristics and OR between high-risk and low-risk groupsPhenotypeMeasuresHigh-risk groupLow-risk groupCrude odds ratiosAdjusted odds ratiosaAdjusted OR calculated using logistic regression to take into account age and sex.n(%)n(%)Any BCC43(39)0(0)Any SCC20(18)0(0)SKNone3(2.5)109(100)> 0108(97)0(0)Facial elastosisNone0(0)109(100)+ +111(100)0(0)Hair colorBlack6(5.5)13(12)Black/dark brown = 1Black/dark brown = 1Dark brown28(26)46(44)Auburn5(4.5)4(4)Red/ginger11(10)2(2)9.04 (1.86, 43.78)bCrude and adjusted OR for risk group were calculated by pooling red/ginger and auburn hair colors.17.96 (2.76, 148.9)bCrude and adjusted OR for risk group were calculated by pooling red/ginger and auburn hair colors.Light brown49(45)33(31)2.44 (1.28, 4.64)Light brown/fair =Fair10(9)7(6)2.35 (0.80, 6.87)1.85 (0.74, 4.61)n = 109n = 105Skin colorOlive0(0)15(14)Olive/medium = 1Olive/medium = 1Medium31(28)49(45)Fair80(72)45(41)2.81 (1.57, 5.02)6.40 (2.56, 16.03)Skin UV responseOnly tans6(5)12(11)11Burns then tans72(65)77(61)1.87 (0.67, 5.25)1.84 (0.69, 4.89)Only burns33(30)20(18)3.30 (1.07, 10.18)9.81 (1.94, 49.54)Back frecklingNone10(9.5)33(31)11+33(32)54(51)2.02 (0.88, 4.62)3.58 (2.02, 6.37)++39(37.5)17(16)7.57 (3.05, 18.78)12.84 (5.69, 28.97)+++22(21)2(2)36.3 (7.25, 181.82)46.01 (16.99, 124.62)n = 104n = 106Age at 199430–49108750–7910122SexMale69(62)38(35)Female42(38)71(65)Total samples111109a Adjusted OR calculated using logistic regression to take into account age and sex.b Crude and adjusted OR for risk group were calculated by pooling red/ginger and auburn hair colors. Open table in a new tab The other major risk factor for BCC and SCC, which was evident in the distinction of the high- and low-risk groups, was pigmentation phenotype. Individuals in the high-risk group were significantly more likely to have light brown or red colored hair. There were too few individuals in this study with fair hair for the difference between study groups to be significant. The small numbers of individuals in the fair hair group was balanced by the excess of individuals reported as light brown when compared with estimates of hair color frequencies in different Caucasian populations (Bliss et al., 1995Bliss J.M. Ford D. Swerdlow A.J. et al.Risk of cutaneous melanoma associated with pigmentation characteristics and freckling: systematic overview of 10 case-control studies. The International Melanoma Analysis Group (IMAGE).Int J Cancer. 1995; 62: 367-376Crossref PubMed Scopus (195) Google Scholar;Palmer et al., 2000Palmer J.S. Duffy D.L. Box N.F. et al.Melanocortin-1 receptor polymorphisms and risk of melanoma: Is the association explained solely by pigmentation phenotype?.Am J Hum Genet. 2000; 66: 176-186https://doi.org/10.1086/302711Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar). This indicates probable reporting differences for fair hair colors between this and other studies. Fair constitutive skin color was also significantly associated with the high-risk grouping (p < 0.0001) as was an increased skin propensity to sunburn. The presence or absence of a solar lesion as the distinguishing feature between the study groups also resulted in obvious age and sex differences between both groups. In the high-risk group 63% were male and the mean age was about 65 y, compared with the low-risk group where the mean age was about 41 y and 38% were male. Although precise age information was available, the large differences in age between the two risk groups prevented extensive correction for this variable. In preliminary analyses, including age as a continuous variable, it was determined that a simple dichotomy at 50 y retained most of the available information for this variable (Table 1). After dichotomizing the age variable at 50 y, pooling hair colors into black/dark brown, light brown/fair, and red/auburn groups, and recategorizing skin color as olive/medium and fair, it was found that only sex exerted an effect on pigmentation phenotype. This was determined by using logistic regression to simultaneously control for age and sex in the association between pigmentation phenotype and risk group with the amalgamation of categories to provide sufficient numbers for analysis. Even after adjusting for age and sex, the associations between risk group and red hair and fair skin color, and skin UV sensitivity remain significant [Table 1, adjusted odds ratios (OR)]. Analysis of MC1R variants in combined high- and low-risk samples revealed significant associations with each phenotype that was scored (Table 2). The ''any'' variant allele category took into account the sum of all nine variants assayed by allele-specific oligonucleotide, expressed as a total of none, one, or two variants. There were no individuals in this study with a total of greater than two variants. The red hair color (''RHC'') variant allele category took into account only the sum of the three variants, which have previously been associated with RHC and melanoma risk: Arg151Cys, Arg160Trp, and Asp294His (Valverde et al., 1995Valverde P. Healy E. Jackson I. Rees J.L. Thody A.J. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans.Nature Genet. 1995; 11: 328-330Crossref PubMed Scopus (796) Google Scholar;Box et al., 1997Box N.F. Wyeth J.R. O'Gorman L.E. Martin N.G. Sturm R.A. Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair.Hum Mol Genet. 1997; 6: 1891-1897https://doi.org/10.1093/hmg/6.11.1891Crossref PubMed Scopus (292) Google Scholar;Smith et al., 1998Smith R. Healy E. Siddiqui S. et al.Melanocortin 1 receptor variants in an Irish population.J Invest Dermatol. 1998; 111: 119-122https://doi.org/10.1046/j.1523-1747.1998.00252.xCrossref PubMed Scopus (215) Google Scholar;Palmer et al., 2000Palmer J.S. Duffy D.L. Box N.F. et al.Melanocortin-1 receptor polymorphisms and risk of melanoma: Is the association explained solely by pigmentation phenotype?.Am J Hum Genet. 2000; 66: 176-186https://doi.org/10.1086/302711Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar).Table 2Association of MC1R variant genotype with scored phenotypesPhenotype Any variantRHC variantsbVariants include R151C, R160W, D294H.OR95% CISignificanceaAll probability values calculated by χ2 comparison of none, one, or two variants for the ''any'' or ''RHC'' categories vs unpooled phenotype divisions. OR were calculated using ''consensus'' and ''one or two variants'' categories, consensus genotype was defined byBox et al. (1997). PT obtained from Mantel–Haenszel test for trend.OR95% CISignificanceHair color Dark brown/black1.001.00 Red/ginger/auburn3.821.05–13.859.883.49–27.88 Light brown1.230.66–2.29p < 0.0043.091.49–6.39p < 0.0001 Fair1.960.59–6.493.080.98–9.68Skin color Olive/medium1.00p < 0.0081.00p = 0.006 Fair1.781.01–3.15PT = 0.0022.411.30–4.48PT = 0.0004Skin response to UV Tans only1.001.00 Burns then tans2.480.92–6.66p = 0.0571.770.49–6.45p = 0.066 Burns only4.271.38–13.23PT < 0.0044.121.07–16.00PT = 0.004Back freckling None1.001.00 +0.790.37–1.701.440.60–3.44 ++1.610.67–3.84p = 0.041.790.71–4.51p < 0.008 +++2.680.77–9.29PT < 0.0053.201.08–9.49PT = 0.008a All probability values calculated by χ2 comparison of none, one, or two variants for the ''any'' or ''RHC'' categories vs unpooled phenotype divisions. OR were calculated using ''consensus'' and ''one or two variants'' categories, consensu
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