Replication of Associations between GWAS SNPs and Melanoma Risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study
2014; Elsevier BV; Volume: 134; Issue: 7 Linguagem: Inglês
10.1038/jid.2014.53
ISSN1523-1747
AutoresJonathan Kocarnik, Sungshim Lani Park, Jiali Han, Logan Dumitrescu, Iona Cheng, Lynne R. Wilkens, Fredrick R. Schumacher, Laurence N. Kolonel, Chris Carlson, Dana C. Crawford, Robert Goodloe, Holli H. Dilks, Paxton Baker, Danielle Richardson, José Luis Ambite, Fengju Song, Abrar A. Quresh, Mingfeng Zhang, David Duggan, Carolyn M. Hutter, Lucia A. Hindorff, William S. Bush, Charles Kooperberg, Loı̈c Le Marchand, Ulrike Peters,
Tópico(s)Cutaneous Melanoma Detection and Management
ResumoEpidemiologic Architecture of Genes Linked to Environment, accessing BioVU, the Biorepository of Vanderbilt University genome-wide association study Health Professionals Follow-up Study Multiethnic Cohort Study Nurses’ Health Study Population Architecture Using Genomics and Epidemiology single nucleotide polymorphism Women’s Health Initiative TO THE EDITOR Melanoma is a considerable public health burden, with an estimated 76,690 new diagnoses and 9,480 deaths from melanoma in the United States in 2013 alone (Howlader et al., 2013Howlader N.N.A. Krapcho M. Garshell J. et al.2013http://seer.cancer.gov/csr/1975_2010/Google Scholar). Multiplex families have pointed to important genetic factors for melanoma, including high-penetrance risk loci such as CDKN2A or CDK4 (Gruber and Armstrong, 2006Gruber S.B. Armstrong B.K. Cutaneous and ocular melanoma.in: Schottenfeld D. Fraumeni J.F. Cancer Epidemiology and Prevention. 3rd. Oxford University Press, USA: New York, NY2006: 1126-1229Crossref Scopus (4) Google Scholar). In sporadic disease, genome-wide association studies (GWAS) have also successfully identified at least eight single nucleotide polymorphisms (SNPs) associated with melanoma (Gerstenblith et al., 2010Gerstenblith M.R. Shi J. Landi M.T. Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis.Pigment Cell Melanoma Res. 2010; 23: 587-606Crossref PubMed Scopus (96) Google Scholar). Our study aimed to replicate these existing GWAS findings within the large Population Architecture using Genomics and Epidemiology (PAGE) study in order to further evaluate their association with melanoma. In addition to genetic factors, other risk factors for melanoma include exposure to natural and artificial UVR, larger numbers of nevi, pigmentation traits (light versus dark hair, eye, and skin color), race/ethnicity (European versus non-European ancestry), skin response to UV exposure (burn versus tan), older age, and male sex (Gruber and Armstrong, 2006Gruber S.B. Armstrong B.K. Cutaneous and ocular melanoma.in: Schottenfeld D. Fraumeni J.F. Cancer Epidemiology and Prevention. 3rd. Oxford University Press, USA: New York, NY2006: 1126-1229Crossref Scopus (4) Google Scholar). Anatomic location of melanoma also tends to vary by sex, arising most commonly on the back, abdomen, and chest in males, and on the lower leg, hip, and thigh in females (Gruber and Armstrong, 2006Gruber S.B. Armstrong B.K. Cutaneous and ocular melanoma.in: Schottenfeld D. Fraumeni J.F. Cancer Epidemiology and Prevention. 3rd. Oxford University Press, USA: New York, NY2006: 1126-1229Crossref Scopus (4) Google Scholar). Females also appear to have lower risk of metastases and longer melanoma-specific survival than males (Joosse et al., 2011Joosse A. de Vries E. Eckel R. et al.Gender differences in melanoma survival: female patients have a decreased risk of metastasis.J Invest Dermatol. 2011; 131: 719-726Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). As melanoma risk, anatomic location, and survival have been shown to vary by sex, this study also aimed to evaluate whether genetic associations with melanoma differed by sex as well. To answer these questions, we evaluated 2,131 invasive melanoma cases and 20,353 melanoma-free controls from five study populations (Supplementary Table S1 online). Three studies collaborated through their participation in the PAGE study (Matise et al., 2011Matise T.C. Ambite J.L. Buyske S. et al.The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study.Am J Epidemiol. 2011; 174: 849-859Crossref PubMed Scopus (120) Google Scholar): the Multiethnic Cohort (MEC), the Women’s Health Initiative (WHI), and Epidemiological Architecture for Genes Linked to Environment (EAGLE), accessing BioVU, the Vanderbilt biorepository linked to de-identified electronic medical records. Two non-PAGE studies also contributed: the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Additional details for these studies are provided in the Supplementary Materials online. All analyses were performed using Stata version 13 (StataCorp LP, College Station, TX). Download .pdf (.71 MB) Help with pdf files Supplementary Material Study-specific logistic regression estimates evaluated the association between each SNP and melanoma, coded additively for each copy of the purported risk allele. These results were combined using fixed effect inverse-weighted meta-analysis to obtain overall effect estimates. The association between a SNP and melanoma was considered statistically significant if the Bonferroni-corrected P-value was below 0.006 (=0.05/8). In order to evaluate for potential sex-specific genetic effects, we also evaluated the association between each SNP and melanoma risk stratified by sex. We performed meta-regression to obtain P-heterogeneity values for the difference between sex-specific regression estimates, using a statistical significance threshold of P-heterogeneity<0.05. All participants were of the European ancestry. HPFS is a male-only study. As NHS and WHI are female-only studies, the overall analysis included roughly twice as many females as males (Supplementary Table S1 online). Melanoma cases tended to be of similar or younger age than controls (overall mean age of 61 in cases vs. 63 in controls), except for in EAGLE-BioVU where controls were older (mean age 64 in cases vs. 56 in controls). We evaluated eight SNPs previously identified by GWAS for an association with melanoma risk (Brown et al., 2008Brown K.M. Macgregor S. Montgomery G.W. et al.Common sequence variants on 20q11.22 confer melanoma susceptibility.Nat Genet. 2008; 40: 838-840Crossref PubMed Scopus (179) Google Scholar; Fernandez et al., 2008Fernandez L.P. Milne R.L. Pita G. et al.SLC45A2: a novel malignant melanoma-associated gene.Hum Mutat. 2008; 29: 1161-1167Crossref PubMed Scopus (91) Google Scholar; Bishop et al., 2009Bishop D.T. Demenais F. Iles M.M. et al.Genome-wide association study identifies three loci associated with melanoma risk.Nat Genet. 2009; 41: 920-925Crossref PubMed Scopus (369) Google Scholar; Falchi et al., 2009Falchi M. Bataille V. Hayward N.K. et al.Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi.Nat Genet. 2009; 41: 915-919Crossref PubMed Scopus (178) Google Scholar; Gerstenblith et al., 2010Gerstenblith M.R. Shi J. Landi M.T. Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis.Pigment Cell Melanoma Res. 2010; 23: 587-606Crossref PubMed Scopus (96) Google Scholar). These SNPs are in or near genes that are likely to be important to melanoma pathways through their potential impact on melanogenesis (TYR, SLC45A2/MATP, AFG3L1P/MC1R, PIGU/ASIP), cell cycle regulation (CDK10), cell growth, and apoptosis (PLA2G6), or tumor suppression (MTAP/CDKN2A). Results from the meta-analyses across 3–5 studies showed seven SNPs statistically significantly associated with melanoma at Bonferroni-corrected levels (meta-analysis P<0.006), whereas the eighth SNP was nominally significant (P=0.02; Table 1). All eight SNPs showed an association in the same direction and of similar magnitude as previously reported. Six of the seven significant SNPs showed a modest increase in melanoma risk (odds ratio (OR)=1.17–1.55), whereas rs16891982 showed a much larger effect (OR=3.11).Table 1Meta-analysis results for the association between eight melanoma GWAS SNPs and melanomaSNPGeneChromosome/risk allelenNo. of studiesOR95% CIP-valueStudy P-heterogeneityrs258322CDK1016/A22,08251.55(1.41–1.70)8.54E-190.62rs4785763AFG3L1P (near MC1R)16/A21,99351.31(1.22–1.40)1.01E-140.73rs16891982SLC45A2 (MATP)5/G15,94933.11(2.31–4.18)7.39E-140.43rs1393350TYR11/A22,00951.25(1.17–1.35)6.21E-100.80rs4636294MTAP (near CDKN2A)9/A22,05351.18(1.11–1.27)5.51E-070.18rs7023329MTAP (near CDKN2A)9/A22,11451.17(1.10–1.25)1.93E-060.36rs910873PIGU (near ASIP)20/A15,93731.31(1.15–1.48)2.46E-051.00rs2284063PLA2G622/G22,08751.09(1.01–1.16)0.0190.27Abbreviations: CI, confidence interval; OR, odds ratio; SNP, single nucleotide polymorphism.Bold P-values are statistically significant for replication at a Bonferroni-corrected threshold of 0.05/8=0.006. SNPs rs16891982 and rs910873 were not available in Health Professionals Follow-up Study (HPFS) or Nurses’ Health Study (NHS). SNPs are ordered by P-value. Open table in a new tab Abbreviations: CI, confidence interval; OR, odds ratio; SNP, single nucleotide polymorphism. Bold P-values are statistically significant for replication at a Bonferroni-corrected threshold of 0.05/8=0.006. SNPs rs16891982 and rs910873 were not available in Health Professionals Follow-up Study (HPFS) or Nurses’ Health Study (NHS). SNPs are ordered by P-value. Sex-stratified analyses showed similar results, with four SNPs significantly associated with melanoma in both male-only and female-only meta-analyses at Bonferroni-corrected levels, and three SNPs nominally associated in each (meta-analysis P<0.05; Supplementary Table S2 online). Only one of these SNPs, rs16891982, showed a potential difference in effect by sex (P-heterogeneity=0.02), with a stronger association in males (OR=5.50, 95% confidence interval (CI): 2.94–10.28) than females (OR=2.37, 95% CI: 1.69–3.31; Table 2, Supplementary Figure S1 online). This non-synonymous SNP in the SLC45A2 gene has previously been associated with melanoma (Fernandez et al., 2008Fernandez L.P. Milne R.L. Pita G. et al.SLC45A2: a novel malignant melanoma-associated gene.Hum Mutat. 2008; 29: 1161-1167Crossref PubMed Scopus (91) Google Scholar; Guedj et al., 2008Guedj M. Bourillon A. Combadieres C. et al.Variants of the MATP/SLC45A2 gene are protective for melanoma in the French population.Hum Mutat. 2008; 29: 1154-1160Crossref PubMed Scopus (57) Google Scholar; Duffy et al., 2010Duffy D.L. Zhao Z.Z. Sturm R.A. et al.Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma.J Invest Dermatol. 2010; 130: 520-528Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar) and pigmentation traits such as skin and hair color (Stokowski et al., 2007Stokowski R.P. Pant P.V. Dadd T. et al.A genomewide association study of skin pigmentation in a South Asian population.Am J Hum Genet. 2007; 81: 1119-1132Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). Also known as MATP, this gene encodes an ion transporter protein in the melanosome. Ion and small-molecule transport is functionally important to melanogenesis and the pigmentation pathway (Scherer and Kumar, 2010Scherer D. Kumar R. Genetics of pigmentation in skin cancer—a review.Mutat Res. 2010; 705: 141-153Crossref PubMed Scopus (144) Google Scholar), as ion exchange is predicted to impact melanogenesis by playing an important role in regulating melanosome pH levels (Kondo and Hearing, 2011Kondo T. Hearing V.J. Update on the regulation of mammalian melanocyte function and skin pigmentation.Expert Rev Dermatol. 2011; 6: 97-108Crossref PubMed Scopus (149) Google Scholar).Table 2Sex-stratified meta-analysis of the association between rs16891982 and melanomaSNPGeneChromosome/risk alleleGroupnNo. of studiesOR95% CIP-valueStudy P-heterogeneitySex P-heterogeneityrs16891982SLC45A25/GFemale10,16032.37(1.69–3.31)4.67E-070.450.02Male5,78925.50(2.94–10.28)9.53E-080.34Abbreviations: CI, confidence interval; OR, odds ratio; SNP, single nucleotide polymorphism.Bold P-values are statistically significant for replication at a Bonferron-corrected threshold of 0.05/8=0.006. SNP rs16891982 was not available in Health Professionals Follow-up Study (HPFS) (male only) or Nurses’ Health Study (NHS) (female only). Open table in a new tab Abbreviations: CI, confidence interval; OR, odds ratio; SNP, single nucleotide polymorphism. Bold P-values are statistically significant for replication at a Bonferron-corrected threshold of 0.05/8=0.006. SNP rs16891982 was not available in Health Professionals Follow-up Study (HPFS) (male only) or Nurses’ Health Study (NHS) (female only). Providing biological plausibility for a potential sex difference, in effect at this SNP, is the evidence that skin pigmentation processes can be up or downregulated by sex hormones. In a recent study of the hyperpigmentation condition melasma, findings supported the role of several ion transporters, including SLC26A3, in the estrogen-induced expression of tyrosinase (Kim et al., 2012Kim N.H. Cheong K.A. Lee T.R. et al.PDZK1 upregulation in estrogen-related hyperpigmentation in melasma.J Invest Dermatol. 2012; 132: 2622-2631Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). In another study, androgens were shown to have an inhibitory effect on tyrosinase activity (Tadokoro et al., 2003Tadokoro T. Rouzaud F. Itami S. et al.The inhibitory effect of androgen and sex-hormone-binding globulin on the intracellular cAMP level and tyrosinase activity of normal human melanocytes.Pigment Cell Res. 2003; 16: 190-197Crossref PubMed Scopus (28) Google Scholar). Tyrosinase is considered the rate-limiting enzyme in melanin synthesis, and regulation of its activity can influence skin pigmentation through the levels of eumelanin and phenomelanin produced (Kondo and Hearing, 2011Kondo T. Hearing V.J. Update on the regulation of mammalian melanocyte function and skin pigmentation.Expert Rev Dermatol. 2011; 6: 97-108Crossref PubMed Scopus (149) Google Scholar). Importantly, both tyrosinase levels and tyrosinase activity have also been associated with rs16891982 genotype (Cook et al., 2009Cook A.L. Chen W. Thurber A.E. et al.Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci.J Invest Dermatol. 2009; 129: 392-405Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). As males and females differ in their circulating levels of sex hormones, it is possible that these hormones impact ion exchange or tyrosinase activity in a way that modifies the effect of this SLC45A2 variant on melanoma risk, perhaps through alterations to melanogenesis or skin pigmentation. Interestingly, sex differences in the genetic effect of solute carrier genes have also been seen for other phenotypes, such as LYPLAL1/SLC30A10 with waist–hip ratio (Randall et al., 2013Randall J.C. Winkler T.W. Kutalik Z. et al.Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.PLoS Genet. 2013; 9: e1003500Crossref PubMed Scopus (271) Google Scholar). Further research is needed to evaluate these potential sex differences in genetic contributions to melanoma risk. This study was strengthened by the collaboration of five large studies, which provide sizable samples to evaluate the melanoma GWAS SNP association with melanoma. Limitations included two SNPs that were not available in HPFS and NHS (rs16891982 and rs910873), though both still replicated. An additional limitation is that we were unable to test whether some of our findings are independently associated with melanoma, or are due to an association with pigmentation characteristics. Additional work will be needed to explore the relationships between these genetic variants, pigmentation characteristics, and melanoma. In summary, this large meta-analysis of five studies successfully replicated seven of eight previous melanoma findings, with the eighth SNP still showing a suggestive effect in the expected direction. In addition, we observed potential differences in effect by sex for SNP rs16891982 in SLC45A2, with a larger effect in males than females. This study reinforces previous evidence that these genetic variants are important for melanoma risk, and for one SNP provides suggestive evidence for a potential sex difference in effect. These results implicate a complex interaction between genetic variants, ion transport, hormones, and pigmentation on melanoma etiology, and demonstrate the potential utility of evaluating sex-specific associations to further elucidate these relationships. (a) The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy.org; (b) The data and materials included in this report results from collaboration between the following studies: The "Epidemiologic Architecture for Genes Linked to Environment (EAGLE)" is funded through the NHGRI PAGE program (U01HG004798-01 and its NHGRI ARRA supplement). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding and by the Vanderbilt CTSA grant, UL1 TR000445, from NCATS/NIH. The Vanderbilt University Center for Human Genetics, Research, Computational Genomics Core provided computational and/or analytical support for this work. The Multiethnic Cohort study (MEC) characterization of epidemiological architecture is funded through the NHGRI PAGE program (U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded through the National Cancer Institute (R37CA54281, R01 CA63464, P01CA33619, U01CA136792, and U01CA98758). Funding support for the “Epidemiology of Putative Genetic Variants: The Women’s Health Initiative” study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination was provided by the PAGE Coordinating Center (U01HG004801-01 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. The Nurses’ Health Study and the Health Professionals Follow-up Study were funded by NIH grants CA122838, CA87969, CA055075, CA49449, CA100264, and CA093459. Funding for work by author JMK was supported by grants R25CA94880 and T32CA09168 from the National Cancer Institute (NCI), NIH. The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid Corrections to: “Replication of Associations between GWAS SNPs and Melanoma Risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study”Journal of Investigative DermatologyVol. 134Issue 11PreviewCorrection to: Journal of Investigative Dermatology (2014) 134, 2049–2052; doi:10.1038/jid.2014.53; published online 27 February 2014 Full-Text PDF Open Archive
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