The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors

Iñigo Landa, Sergio Ruiz-Llorente, Cristina Montero-Conde, Lucía Inglada-Pérez, Francesca Schiavi, Susanna Leskelä, Guillermo Pita, Roger Milne, Javier Maravall, Ignacio Ramos, Víctor Andía, Paloma Rodríguez-Poyo, Antonino Jara-Albarrán, Amparo Meoro, Cristina Del Peso, Luis Arribas, Pedro Iglesias, Javier Caballero, Joaquín Serrano, Antonio PicóFrancisco Pomares, Gabriel Giménez, Pedro López-Mondéjar, Roberto Castello, Isabella Merante-Boschin, Maria Rosa Pelizzo, Didac Mauricio, Giuseppe Opocher, Cristina Rodríguez-Antona, Anna González-Neira, Xavier Matías-Guiu, Pilar Santisteban, Mercedes Robledo

Research output: Contribution to journalArticlepeer-review

Abstract

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology froma single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9×10-9). Functional assays of rs1867277 (NM-004473.3:c.-283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

Original languageEnglish
Article numbere1000637
JournalPLoS Genetics
Volume5
Issue number9
DOIs
Publication statusPublished - Sep 2009

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

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