title: Replication and predictive value of SNPs associated with melanoma and pigmentation traits in a Southern European case-control study.
abstract: BACKGROUND
  Genetic association studies have revealed numerous polymorphisms conferring susceptibility to melanoma. We aimed to replicate previously discovered melanoma-associated single-nucleotide polymorphisms (SNPs) in a Greek case-control population, and examine their predictive value.
  
  
  METHODS
  Based on a field synopsis of genetic variants of melanoma (MelGene), we genotyped 284 patients and 284 controls at 34 melanoma-associated SNPs of which 19 derived from GWAS. We tested each one of the 33 SNPs passing quality control for association with melanoma both with and without accounting for the presence of well-established phenotypic risk factors. We compared the risk allele frequencies between the Greek population and the HapMap CEU sample. Finally, we evaluated the predictive ability of the replicated SNPs.
  
  
  RESULTS
  Risk allele frequencies were significantly lower compared to the HapMap CEU for eight SNPs (rs16891982--SLC45A2, rs12203592--IRF4, rs258322--CDK10, rs1805007--MC1R, rs1805008--MC1R, rs910873--PIGU, rs17305573--PIGU, and rs1885120--MTAP) and higher for one SNP (rs6001027--PLA2G6) indicating a different profile of genetic susceptibility in the studied population. Previously identified effect estimates modestly correlated with those found in our population (r = 0.72, P<0.0001). The strongest associations were observed for rs401681-T in CLPTM1L (odds ratio [OR] 1.60, 95% CI 1.22-2.10; P = 0.001), rs16891982-C in SCL45A2 (OR 0.51, 95% CI 0.34-0.76; P = 0.001), and rs1805007-T in MC1R (OR 4.38, 95% CI 2.03-9.43; P = 2×10⁻⁵). Nominally statistically significant associations were seen also for another 5 variants (rs258322-T in CDK10, rs1805005-T in MC1R, rs1885120-C in MYH7B, rs2218220-T in MTAP and rs4911442-G in the ASIP region). The addition of all SNPs with nominal significance to a clinical non-genetic model did not substantially improve melanoma risk prediction (AUC for clinical model 83.3% versus 83.9%, p = 0.66).
  
  
  CONCLUSIONS
  Overall, our study has validated genetic variants that are likely to contribute to melanoma susceptibility in the Greek population.
authors: Department of Dermatology, University of Athens Medical School, Andreas Sygros Hospital, Athens, Greece.
authors: Irene
authors: I
authors: Stefanaki
authors: Orestis A
authors: OA
authors: Panagiotou
authors: Elisavet
authors: E
authors: Kodela
authors: Helen
authors: H
authors: Gogas
authors: Katerina P
authors: KP
authors: Kypreou
authors: Foteini
authors: F
authors: Chatzinasiou
authors: Vasiliki
authors: V
authors: Nikolaou
authors: Michaela
authors: M
authors: Plaka
authors: Iro
authors: I
authors: Kalfa
authors: Christina
authors: C
authors: Antoniou
authors: John P A
authors: JP
authors: Ioannidis
authors: Evangelos
authors: E
authors: Evangelou
authors: Alexander J
authors: AJ
authors: Stratigos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010858:Pigmentation / Q000235:genetics / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
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