Association of Melanocortin-1 Receptor Variants with Pigmentary Traits in Humans: A Pooled Analysis from the M-Skip Project
2016; Elsevier BV; Volume: 136; Issue: 9 Linguagem: Inglês
10.1016/j.jid.2016.05.099
ISSN1523-1747
AutoresElena Tagliabue, Sara Gandini, José C. García‐Borrón, Patrick Maisonneuve, Julia Newton‐Bishop, David Polsky, DeAnn Lazovich, Rajiv Kumar, Paola Ghiorzo, Leah M. Ferrucci, Nelleke A. Gruis, Susana Puig, Peter A. Kanetsky, Tomonori Motokawa, Glòria Ribas, Maria Teresa Landi, Maria Concetta Fargnoli, Terence H Wong, Alexander Stratigos, Per Helsing, Gabriella Guida, Philippe Autier, Jiali Han, Julian Little, Francesco Sera, Sara Raimondi, Sara Raimondi, Philippe Autier, Maria Concetta Fargnoli, José C. García-Borrón, Jiali Han, Peter A. Kanetsky, Maria Teresa Landi, Julian Little, Julia Newton-Bishop, Francesco Sera, Saverio Caini, Sara Gandini, Patrick Maisonneuve, Albert Hofman, Manfred Kayser, Fan Liu, Tamar Nijsten, Andre G. Uitterlinden, Rajiv Kumar, Dominique Scherer, D. Timothy Bishop, Julia Newton-Bishop, Faye Elliott, Eduardo Nagore, DeAnn Lazovich, David Polsky, Johan Hansson, Veronica Höiom, Paola Ghiorzo, Lorenza Pastorino, Nelleke A. Gruis, Jan Nico Bouwes Bavinck, Paula Aguilera, Célia Bádenas, Cristina Carrera, Pol Giménez‐Xavier, Josep Malvehy, Míriam Potrony, Susana Puig, Susana Puig, Gemma Tell‐Martí, Terence Dwyer, Leigh Blizzard, Jennifer Cochrane, Ricardo Fernández‐de‐Misa, Wojciech Branicki, Tadeusz Dębniak, Niels Morling, Peter Johansen, Susan T. Mayne, A. Bale, Brenda Cartmel, Leah M. Ferrucci, Ruth M. Pfeiffer, Giuseppe Palmieri, Glòria Ribas, Chiara Menin, Alexander Stratigos, K. Kypreou, A. Bowcock, Lynn A. Cornelius, M. Laurin Council, Tomonori Motokawa, Sumiko Anno, Per Helsing, Per Arne Andresen, Gabriella Guida, Stefania Guida, Terence H Wong,
Tópico(s)Skin Protection and Aging
ResumoSkin pigmentation is due to the accumulation of eumelanin, which is brown-black pigment and photoprotective, and pheomelanin, which is yellow-red pigment and may promote carcinogenesis (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.Nat Genet. 1995; 11: 328-330Crossref PubMed Scopus (837) Google Scholar). The melanocortin-1 receptor (MC1R) gene regulates the amount and type of pigment production and is a major determinant of skin phototype (Garcia-Borron et al., 2005Garcia-Borron J.C. Sanchez-Laorden B.L. Jimenez-Cervantes C. Melanocortin-1 receptor structure and functional regulation.Pigment Cell Res. 2005; 18: 393-410PubMed Google Scholar, 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.Nat Genet. 1995; 11: 328-330Crossref PubMed Scopus (837) Google Scholar). Binding of α-melanocyte stimulating hormone to MC1R stimulates the enzymatic activity of adenylate cyclase enzyme, thereby elevating intracellular cyclic adenosine monophosphate (cAMP) levels. MC1R is highly polymorphic, especially in Caucasians: more than 200 coding region variants have been described to date (Garcia-Borron et al., 2014Garcia-Borron J.C. Abdel-Malek Z. Jimenez-Cervantes C. MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation.Pigment Cell Melanoma Res. 2014; 27: 699-720Crossref PubMed Scopus (127) Google Scholar, Gerstenblith et al., 2007Gerstenblith M.R. Goldstein A.M. Fargnoli M.C. Peris K. Landi M.T. Comprehensive evaluation of allele frequency differences of MC1R variants across populations.Hum Mutat. 2007; 28: 495-505Crossref PubMed Scopus (126) Google Scholar, Perez Oliva et al., 2009Perez Oliva A.B. Fernendez L.P. Detorre C. Herraiz C. Martinez-Escribano J.A. Benitez J. et al.Identification and functional analysis of novel variants of the human melanocortin 1 receptor found in melanoma patients.Hum Mutat. 2009; 30: 811-822Crossref PubMed Scopus (48) Google Scholar). Six variants—D84E, R142H, R151C, I155T, R160W, and D294H—have been designated as "R" alleles because of their strong association with the "red hair color" phenotype characterized by red hair, fair skin, freckles, and sun sensitivity. The V60L, V92M, and R163Q variants are found to have a weaker association with the red hair color phenotype and have been designated as "r" alleles (Garcia-Borron et al., 2014Garcia-Borron J.C. Abdel-Malek Z. Jimenez-Cervantes C. MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation.Pigment Cell Melanoma Res. 2014; 27: 699-720Crossref PubMed Scopus (127) Google Scholar, Raimondi et al., 2008Raimondi S. Sera F. Gandini S. Iodice S. Caini S. Maisonneuve P. et al.MC1R variants, melanoma and red hair color phenotype: a meta-analysis.Int J Cancer. 2008; 122: 2753-2760Crossref PubMed Scopus (266) Google Scholar). Previous studies demonstrated that several alleles are associated with phenotypic characteristics and that MC1R variants are associated with both melanoma and nonmelanoma skin cancer (Han et al., 2006Han J. Kraft P. Colditz G.A. Wong J. Hunter D.J. Melanocortin 1 receptor variants and skin cancer risk.Int J Cancer. 2006; 119: 1976-1984Crossref PubMed Scopus (107) Google Scholar, Pasquali et al., 2015Pasquali E. Garcia-Borron J.C. Fargnoli M.C. Gandini S. Maisonneuve P. Bagnardi V. et al.MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: a pooled-analysis from the M-SKIP project.Int J Cancer. 2015; 136: 618-631PubMed Google Scholar, Scherer et al., 2008Scherer D. Bermejo J.L. Rudnai P. Gurzau E. Koppova K. Hemminki K. et al.MC1R variants associated susceptibility to basal cell carcinoma of skin: interaction with host factors and XRCC3 polymorphism.Int J Cancer. 2008; 122: 1787-1793Crossref PubMed Scopus (50) Google Scholar, Tagliabue et al., 2015Tagliabue E. Fargnoli M.C. Gandini S. Maisonneuve P. Liu F. Kayser M. et al.MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.Br J Cancer. 2015; 113: 354-363Crossref PubMed Scopus (29) Google Scholar) with a stronger role for darker-pigmented populations, suggesting that nonpigmentary pathways link MC1R with skin cancer development. Because the role and strength of each MC1R variant in determining specific phenotypic characteristics and the red hair color phenotype remains unclear, we performed a pooled analysis of individual-level data from the M-SKIP project, described in full elsewhere (Raimondi et al., 2012Raimondi S. Gandini S. Fargnoli M.C. Bagnardi V. Maisonneuve P. Specchia C. et al.Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project: study design and methods for pooling results of genetic epidemiological studies.BMC Med Res Methodol. 2012; 12: 116Crossref PubMed Scopus (11) Google Scholar). We selected from the M-SKIP database all 5,366 cancer-free controls with MC1R gene sequenced and information on at least one of the following phenotypic characteristics: hair color, eye color, skin type, and freckles, thus including 16 independent studies from 18 publications (Supplementary Table S1 online). We found greater summary odds ratios (SORs) for carriers of two MC1R variants compared with carriers of only one variant allele (Table 1). Furthermore carriage of any MC1R variant, one variant and two or more variants, compared with not having such variants (i.e., wild-type [WT] subjects), was significantly associated with fair hair color, skin type I/II, and presence of freckles. Red hair color was significantly associated with carrying any MC1R variant (SOR; 95% confidence interval: 3.54; 1.91–6.55) and with carrying two or more variants (SOR; 95% confidence interval: 10.17; 5.28–19.58), but not with carrying one MC1R variant (SOR; 95% confidence interval: 1.18; 0.57–2.44). No significant association was observed for light eye color and MC1R. Sensitivity analyses indicated that the observed between-study heterogeneity may be attributable to single studies: when we excluded the studies that were outliers, we obtained similar pooled odds ratios as the original ones, but no longer with evidence of heterogeneity (results not shown). No evidence of publication bias was found by Egger's test. All the investigated MC1R variants compared with WT subjects were positively associated with skin type I/II and freckles (Supplementary Table S2 online). The three variants that seemed to play the most important role in skin type determination and the presence of freckles were D84E, R151C, and D294H. Red hair color was significantly associated with all MC1R variants except for V92M and R163Q.Table 1Summary odds ratios for the association between combined MC1R variants and phenotypic characteristicsPhenotypic characteristicMC1RStudies/controlSOR (95% CI)I2 (%)3I2 and Q test P-value are measures of between-study heterogeneity (see Supplementary Methods online).P-value3I2 and Q test P-value are measures of between-study heterogeneity (see Supplementary Methods online).Hair color—fair versus dark1Fair hair colors were red, blond, dark blonde, light brown. Dark hair colors were brown, black, dark brown.Wild-type13/1,3711.00 (reference)Any variant13/2,7581.91 (1.38–2.65)59<0.011 variant13/1,9911.55 (1.12–2.15)390.072+ variants13/7673.32 (2.34–4.72)62<0.01Hair color—red versus othersWild-type7/7051.00 (reference)Any variant7/1,4743.54 (1.91–6.55)00.801 variant7/1,0161.18 (0.57–2.44)00.832+ variants7/45810.17 (5.28–19.58)00.77Eye color—fair versus dark2Fair eye colors were blue, green, gray, hazel. Dark eye colors were brown, black.Wild-type14/1,5301.00 (reference)Any variant14/2,8321.12 (0.96–1.30)120.331 variant14/2,0791.11 (0.94–1.32)100.352+ variants14/7531.16 (0.93–1.45)00.80Skin type—I, II versus III, IVWild-type14/1,5401.00 (reference)Any variant14/3,0462.26 (1.81–2.83)490.021 variant14/2,2111.95 (1.51–2.53)410.062+ variants14/8,353.58 (2.68–4.78)420.05Freckles—yes versus noWild-type9/1,0671.00 (reference)Any variant9/2,2572.52 (1.99–3.20)330.161 variant9/1,5282.00 (1.52–2.64)360.132+ variants9/7294.47 (3.25–6.15)380.12Significant ORs and P-values are in bold.Abbreviations: CI, confidence intervals; MC1R, melanocortin-1 receptor; OR, odds ratio; SOR, summary odds ratio.1 Fair hair colors were red, blond, dark blonde, light brown. Dark hair colors were brown, black, dark brown.2 Fair eye colors were blue, green, gray, hazel. Dark eye colors were brown, black.3 I2 and Q test P-value are measures of between-study heterogeneity (see Supplementary Methods online). Open table in a new tab Significant ORs and P-values are in bold. Abbreviations: CI, confidence intervals; MC1R, melanocortin-1 receptor; OR, odds ratio; SOR, summary odds ratio. We visualized the associations between hair color, eye color, skin type, freckles, and the three main studied geographical areas by multiple correspondence analysis (Supplementary Figure S1a or b online). A two-dimensional multiple correspondence analysis solution, with dimension 1 on the horizontal axis and dimension 2 on the vertical axis, was considered the most adequate because the first and second dimension presented Benzecri-adjusted inertias of 85.31% and 11.31%, respectively (Supplementary Table S3 online), accounting for 96.62% of the total association. The extreme red hair color phenotype (red hair, skin type I, and freckles) was associated either with carrying at least two MC1R variants (Supplementary Figure S1a) or with the presence of major penetrant ("R") alleles (Supplementary Figure S1b). We suggest that dimension 1 can be interpreted as a "pigmentation score" because it differentiates well between dark and fair phenotypic characteristics. The median pigmentation score increased with increasing number of MC1R variants, and for single MC1R variants it was higher (P < 0.0001) compared with WT subjects (Supplementary Figure S2 online). Seven of the nine MC1R variants analyzed in this study, V60L, D84E, R142H, R151C, I155T, R160W, and D294H, are clearly hypomorphic with significant reduction in cAMP signaling potential (Beaumont et al., 2007Beaumont K.A. Shekar S.N. Newton R.A. James M.R. Stow J.L. Duffy D.L. et al.Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles.Hum Mol Genet. 2007; 16: 2249-2260Crossref PubMed Scopus (134) Google Scholar, Herraiz et al., 2012Herraiz C. Journe F. Ghanem G. Jimenez-Cervantes C. Garcia-Borron J.C. Functional status and relationships of melanocortin 1 receptor signaling to the cAMP and extracellular signal-regulated protein kinases 1 and 2 pathways in human melanoma cells.Int J Biochem Cell Biol. 2012; 44: 2244-2252Crossref PubMed Scopus (24) Google Scholar, Kadekaro et al., 2010Kadekaro A.L. Leachman S. Kavanagh R.J. Swope V. Cassidy P. Supp D. et al.Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation.FASEB J. 2010; 24: 3850-3860Crossref PubMed Scopus (101) Google Scholar, Scott et al., 2002Scott M.C. Wakamatsu K. Ito S. Kadekaro A.L. Kobayashi N. Groden J. et al.Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation.J Cell Sci. 2002; 115: 2349-2355PubMed Google Scholar). Within this group of variants, the lowest SOR for red hair, skin type I/II, or freckles corresponds to V60L. Interestingly, this variant was also the one with the smallest functional impairment in terms of coupling to the cAMP pathway, when the seven variants analyzed here were compared under identical experimental conditions (Herraiz et al., 2012Herraiz C. Journe F. Ghanem G. Jimenez-Cervantes C. Garcia-Borron J.C. Functional status and relationships of melanocortin 1 receptor signaling to the cAMP and extracellular signal-regulated protein kinases 1 and 2 pathways in human melanoma cells.Int J Biochem Cell Biol. 2012; 44: 2244-2252Crossref PubMed Scopus (24) Google Scholar). Results also showed that V92M and R163Q behave as "r" alleles, with a weak albeit significant association with cutaneous phenotypic traits. In heterologous systems, V92M has been reported to display either a slight functional impairment (Herraiz et al., 2012Herraiz C. Journe F. Ghanem G. Jimenez-Cervantes C. Garcia-Borron J.C. Functional status and relationships of melanocortin 1 receptor signaling to the cAMP and extracellular signal-regulated protein kinases 1 and 2 pathways in human melanoma cells.Int J Biochem Cell Biol. 2012; 44: 2244-2252Crossref PubMed Scopus (24) Google Scholar) or normal coupling to the cAMP pathway (Beaumont et al., 2007Beaumont K.A. Shekar S.N. Newton R.A. James M.R. Stow J.L. Duffy D.L. et al.Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles.Hum Mol Genet. 2007; 16: 2249-2260Crossref PubMed Scopus (134) Google Scholar), whereas R163Q apparently signals as efficiently as WT. Therefore, it appears that the ability of V92M or R163Q to activate the cAMP pathway is similar, if not identical to WT. This suggests that other mechanisms account for their association with cutaneous phenotypic characteristics, for example, V92M or R163Q might impair functional coupling to signaling module(s) different from the cAMP cascade. MC1R promiscuously binds to a variety of intracellular partners with signaling potential and this ability might depend on WT conformation. However, little is known as to the effects of other variants on MC1R binding to its various protein partners, and the phenotypic consequences of such molecular interactions also remain largely unknown. Further research is needed to understand the scaffolding properties of MC1R, the functional consequences of the formation of signaling complexes orchestrated by the receptor, and the effects on these processes of the myriad of natural variants in the MC1R gene. Leah Ferrucci: http://orcid.org/0000-0001-9488-7586 The authors state no conflicts of interest. This work was supported by the Italian Association for Cancer Research (grant number: MFAG 11831). The Melanoma Susceptibility Study (PAK) was supported by the National Cancer Institute [CA75434, CA80700, and CA092428]. The Nurses' Health Study and the Health Professionals Follow-Up Study (JH) were supported by NIH R01 CA49449, P01 CA87969, UM1 CA186107, and UM1 CA167552. We would like to thank the participants and staff of the Nurses' Health Study, the Health Professionals Follow-Up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. Genoa study was supported by AIRC IG 15460 to PG. The M-SKIP study group consists of the following members: Principal Investigator (PI): Sara Raimondi (European Institute of Oncology, Milan, Italy); Advisory Committee members: Philippe Autier (International Prevention Research Institute, Lyon, France), Maria Concetta Fargnoli (University of L'Aquila, Italy), José C. García-Borrón (University of Murcia, Spain), Jiali Han (Brigham and Women's Hospital and Harvard Medical School, Boston, MA), Peter A. Kanetsky (Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL), Maria Teresa Landi (National Cancer Institute, NIH, Bethesda, MD), Julian Little (University of Ottawa, Canada), Julia Newton-Bishop (University of Leeds, UK), Francesco Sera (UCL Institute of Child Health, London, UK); Consultants: Saverio Caini (ISPO, Florence, Italy), Sara Gandini and Patrick Maisonneuve (European Institute of Oncology, Milan, Italy); Participant Investigators: Albert Hofman, Manfred Kayser, Fan Liu, Tamar Nijsten, and Andre G. Uitterlinden (Erasmus MC University Medical Center, Rotterdam, The Netherlands), Rajiv Kumar and Dominique Scherer (German Cancer Research Center, Heidelberg, Germany), Tim Bishop, Julia Newton-Bishop, and Faye Elliott (University of Leeds, UK), Eduardo Nagore (Instituto Valenciano de Oncologia, Valencia, Spain), DeAnn Lazovich (Division of Epidemiology and Community Health, University of Minnesota, MN), David Polsky (New York University School of Medicine, New York, NY), Johan Hansson and Veronica Hoiom (Karolinska Institutet, Stockholm, Sweden), Paola Ghiorzo and Lorenza Pastorino (University of Genoa, Italy), Nelleke A. Gruis and Jan Nico Bouwes Bavinck (Leiden University Medical Center, The Netherlands), Paula Aguilera, Celia Badenas, Cristina Carrera, Pol Gimenez-Xavier, Josep Malvehy, Miriam Potrony, Susana Puig, Joan Anton Puig-Butille, Gemma Tell-Marti (Hospital Clinic, IDIBAPS and CIBERER, Barcelona, Spain), Terence Dwyer (Murdoch Childrens Research Institute, Victoria, Australia), Leigh Blizzard and Jennifer Cochrane (Menzies Institute for Medical Research, Hobart, Australia), Ricardo Fernandez-de-Misa (Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain), Wojciech Branicki (Institute of Forensic Research, Krakow, Poland), Tadeusz Debniak (Pomeranian Medical University, Polabska, Poland), Niels Morling and Peter Johansen (University of Copenhagen, Denmark), Susan Mayne, Allen Bale, Brenda Cartmel and Leah Ferrucci (Yale School of Public Health and Medicine, New Haven, CT), Ruth Pfeiffer (National Cancer Institute, NIH, Bethesda, MD), Giuseppe Palmieri (Istituto di Chimica Biomolecolare, CNR, Sassari, Italy), Gloria Ribas (Fundación Investigación Clínico de Valencia Instituto de Investigación Sanitaria- INCLIVA, Spain), Chiara Menin (Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy), Alexander Stratigos and Katerina Kypreou (University of Athens, Andreas Sygros Hospital, Athens, Greece), Anne Bowcock, Lynn Cornelius, and M. Laurin Council (Washington University School of Medicine, St. Louis, MO), Tomonori Motokawa (POLA Chemical Industries, Yokohama, Japan), Sumiko Anno (Shibaura Institute of Technology, Tokyo, Japan), Per Helsing and Per Arne Andresen (Oslo University Hospital, Norway), Gabriella Guida and Stefania Guida (University of Bari, Bari, Italy), Terence H. Wong (University of Edinburgh, UK), and the GEM Study Group. Participants in the GEM Study Group are as follows: Coordinating Center, Memorial Sloan-Kettering Cancer Center, New York, NY: Marianne Berwick (PI, currently at the University of New Mexico), Colin Begg (Co-PI), Irene Orlow (Co-Investigator), Urvi Mujumdar (Project Coordinator), Amanda Hummer (Biostatistician), Klaus Busam (Dermatopathologist), Pampa Roy (Laboratory Technician), Rebecca Canchola (Laboratory Technician), Brian Clas (Laboratory Technician), Javiar Cotignola (Laboratory Technician), Yvette Monroe (Interviewer). Study Centers: The University of Sydney and The Cancer Council New South Wales, Sydney (Australia): Bruce Armstrong (PI), Anne Kricker (co-PI), Melisa Litchfield (Study Coordinator). Menzies Institute for Medical Research, University of Tasmania, Hobart (Australia): Terence Dwyer (PI), Paul Tucker (Dermatopathologist), Nicola Stephens (Study Coordinator). British Columbia Cancer Agency, Vancouver (Canada): Richard Gallagher (PI), Teresa Switzer (Coordinator). Cancer Care Ontario, Toronto (Canada): Loraine Marrett (PI), Beth Theis (Co-Investigator), Lynn From (Dermatopathologist), Noori Chowdhury (Coordinator), Louise Vanasse (Coordinator), Mark Purdue (Research Officer). David Northrup (Manager for CATI). Centro per la Prevenzione Oncologia Torino, Piemonte (Italy): Roberto Zanetti (PI), Stefano Rosso (Data Manager), Carlotta Sacerdote (Coordinator). University of California, Irvine, CA: Hoda Anton-Culver (PI), Nancy Leighton (Coordinator), Maureen Gildea (Data Manager). University of Michigan, Ann Arbor, MI: Stephen Gruber (PI), Joe Bonner (Data Manager), Joanne Jeter (Coordinator). New Jersey Department of Health and Senior Services, Trenton, NJ: Judith Klotz (PI), Homer Wilcox (Co-PI), Helen Weiss (Coordinator). University of North Carolina, Chapel Hill, NC: Robert Millikan (PI), Nancy Thomas (Co-Investigator), Dianne Mattingly (Coordinator), Jon Player (Laboratory Technician), Chiu-Kit Tse (Data Analyst). University of Pennsylvania, Philadelphia, PA: Timothy Rebbeck (PI), Peter Kanetsky (Co-Investigator), Amy Walker (Laboratory Technician), Saarene Panossian (Laboratory Technician). Consultants: Harvey Mohrenweiser, University of California, Irvine, Irvine, CA; Richard Setlow, Brookhaven National Laboratory, Upton, NY. Download .pdf (.26 MB) Help with pdf files Supplementary Data
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