ABSTRACT
The skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.
Subject(s)
Carrier Proteins/genetics , Genetic Loci , Neoplasm Proteins/genetics , Receptors, Aryl Hydrocarbon/genetics , Sunburn/genetics , Suntan/genetics , White People/genetics , Adult , Aged , Chromosome Mapping , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Hair Color/genetics , Humans , Male , Melanoma/etiology , Melanoma/genetics , Middle Aged , Neoplasms, Radiation-Induced/genetics , Phenotype , Polymorphism, Single Nucleotide , Prospective Studies , Radiation Exposure , Risk Factors , Sex Factors , Skin Neoplasms/etiology , Skin Neoplasms/genetics , United KingdomABSTRACT
Growing evidence suggests that some individuals may exhibit symptoms of dependence to ultraviolet light, a known carcinogen, in the context of tanning. Genetic associations with tanning dependence (TD) have not yet been explored. We conducted an exome-wide association study in 79 individuals who exhibited symptoms of TD and 213 individuals with volitional exposure to ultraviolet light, but who were not TD based on three TD scales. A total of 300 000 mostly exomic single nucleotide polymorphisms primarily in coding regions were assessed using an Affymetrix Axiom array. We performed a gene burden test with Bonferroni correction for the number of genes examined (P < 0.05/14 904 = 3.36 × 10(-6) ). One gene, patched domain containing 2 (PTCHD2), yielded a statistically significant P-value of 2.5 × 10(-6) (OR = 0.27) with fewer individuals classified as TD having a minor allele at this locus. These results require replication, but are the first to support a specific genetic association with TD.
Subject(s)
Membrane Proteins/genetics , Mental Disorders/genetics , Polymorphism, Single Nucleotide , Sunbathing/psychology , Suntan/genetics , Alleles , Carcinoma, Basal Cell/etiology , Carcinoma, Basal Cell/genetics , Case-Control Studies , Exons , Genetic Association Studies , Humans , Neoplasms, Radiation-Induced/etiology , Neoplasms, Radiation-Induced/genetics , Risk Factors , Skin Neoplasms/etiology , Skin Neoplasms/geneticsABSTRACT
The production of pigment by melanocytes tans the skin and protects against skin cancers. UV-exposed keratinocytes secrete α-MSH, which then activates melanin formation in melanocytes by inducing the microphthalmia-associated transcription factor (MITF). We show that PPAR-γ coactivator (PGC)-1α and PGC-1ß are critical components of this melanogenic system in melanocytes. α-MSH signaling strongly induces PGC-1α expression and stabilizes both PGC-1α and PGC-1ß proteins. The PGC-1s in turn activate the MITF promoter, and their expression correlates strongly with that of MITF in human melanoma cell lines and biopsy specimens. Inhibition of PGC-1α and PGC-1ß blocks the α-MSH-mediated induction of MITF and melanogenic genes. Conversely, overexpression of PGC-1α induces pigment formation in cell culture and transgenic animals. Finally, polymorphism studies reveal expression quantitative trait loci in the PGC-1ß gene that correlate with tanning ability and protection from melanoma in humans. These data identify PGC-1 coactivators as regulators of human tanning.
Subject(s)
Carrier Proteins/physiology , Heat-Shock Proteins/physiology , Melanoma/metabolism , Microphthalmia-Associated Transcription Factor/metabolism , Skin Neoplasms/metabolism , Suntan/genetics , Transcription Factors/physiology , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Case-Control Studies , Cell Line, Tumor , Gene Expression , Genetic Association Studies , Genetic Predisposition to Disease , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Humans , Keratinocytes/metabolism , Keratinocytes/radiation effects , Melanins/biosynthesis , Melanocytes/enzymology , Melanocytes/metabolism , Melanoma/genetics , Melanoma/pathology , Mice , Mice, Inbred C57BL , Microphthalmia-Associated Transcription Factor/genetics , Monophenol Monooxygenase/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Protein Stability , RNA-Binding Proteins , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Transcription Factors/genetics , Transcription Factors/metabolism , Transcriptional Activation , alpha-MSH/metabolism , alpha-MSH/physiologyABSTRACT
UV-induced melanogenesis (tanning) and "premature aging" or photoaging result in large part from DNA damage. This article reviews data tying both phenomena to telomere-based DNA damage signaling and develops a conceptual framework in which both responses may be understood as cancer-avoidance protective mechanisms.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 25-31; doi:10.1038/jidsymp.2009.9.
