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

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2009
Author
Landa, Iñigo
Ruiz-Llorente, Sergio
Montero-Conde, Cristina
Inglada-Pérez, Lucía
Schiavi, Francesca
Leskelä, Susanna
Pita, Guillermo
Milne, Roger
Maravall Royo, Javier
Ramos, Ignacio
Andía, Víctor
Rodríguez-Poyo, Paloma
Jara-Albarrán, Antonino
Meoro, Amparo
Peso, Cristina del
Arribas, Luis
Iglesias, Pedro
Caballero, Javier
Serrano, Joaquín
Picó, Antonio
Pomares, Francisco
Giménez, Gabriel
López-Mondéjar, Pedro
Castello, Roberto
Merante-Boschin, Isabella
Pelizzo, Maria-Rosa
Mauricio Puente, Dídac
Opocher, Giuseppe
Rodríguez-Antona, Cristina
González- Neira, Anna
Matias-Guiu, Xavier
Santisteban, Pilar
Robledo, Mercedes
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Landa, Iñigo; Ruiz-Llorente, Sergio; Montero-Conde, Cristina; Inglada-Pérez, Lucía; Schiavi, Francesca; Leskelä, Susanna; ... Robledo, Mercedes. (2009) . The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors. PLoS Genetics, 2009, vol. 5, núm. 9, e1000637. https://doi.org/10.1371/journal.pgen.1000637.
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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[perallele] = 1.49; 95%CI = 1.30–1.70; P = 5.961029). Functional assays of rs1867277 (NM_004473.3:c.2283G.A) within the FOXE1 59 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/aCREM 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.
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http://hdl.handle.net/10459.1/48271
DOI
https://doi.org/10.1371/journal.pgen.1000637
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PLoS Genetics, 2009, vol. 5, núm. 9, e1000637
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