The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.
The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.
复制标题
DOI：
10.1371/journal.pgen.1000637
复制
发表时间：
2009-09
期刊：
影响因子：
4.5
通讯作者：
Robledo M
中科院分区：
文献类型：
--
作者：
Landa I;Ruiz-Llorente S;Montero-Conde C;Inglada-Pérez L;Schiavi F;Leskelä S;Pita G;Milne R;Maravall J;Ramos I;Andía V;Rodríguez-Poyo P;Jara-Albarrán A;Meoro A;del Peso C;Arribas L;Iglesias P;Caballero J;Serrano J;Picó A;Pomares F;Giménez G;López-Mondéjar P;Castello R;Merante-Boschin I;Pelizzo MR;Mauricio D;Opocher G;Rodríguez-Antona C;González-Neira A;Matías-Guiu X;Santisteban P;Robledo M
为了确定与甲状腺癌易感性相关的遗传因素，我们采用了候选基因的方法。我们研究了甲状腺细胞分化和增殖相关基因的标签和推定功能性SNP，以及甲状腺癌中差异表达的基因。在西班牙的615例病例和525例对照中，对97个基因中的768个SNP进行了基因分型，前者包括迄今为止研究的单一人群中最大的这种病理学患者集合。跨越整个FOXE 1基因的LD块中的SNPs显示出与甲状腺乳头状癌易感性相关的最强证据。这种关联在研究的第二阶段得到了验证，该研究包括一个独立的意大利系列的482名患者和532名对照。rs1867277的关联性最强（OR [每等位基因]= 1.49; 95%CI = 1.30 - 1.70; P = 5.9 × 10 − 9）。 FOXE 1 5 ′ UTR内的rs1867277（NM_004473.3：c. − 283G> A）的功能分析表明，该变体影响FOXE 1的转录。DNA结合试验表明，仅含有A等位基因的序列募集USF1/USF2转录因子，而两个等位基因形成DREAM/CREB/α CREM参与的复合物。转染研究表明，等位基因依赖的转录调控FOXE 1。我们提出了一个依赖于rs1867277基因型的FOXE 1调控模型，表明该SNP是甲状腺癌易感性的一个因果变异。我们的研究结果构成了第一个功能性解释的关联确定的GWAS，从而阐明了甲状腺癌易感性的机制。他们还证明了GWAS时代候选基因方法的有效性。虽然滤泡细胞衍生的甲状腺癌有一个重要的遗传成分，在确定主要易感基因的努力还没有成功。这可能是由于这种疾病的复杂性，涉及遗传和环境因素，以及它们之间的相互作用，这可能最终调节个体的易感性。在这项研究中，重点关注通过其与疾病的生物学关系精心选择的基因，并使用来自两个独立高加索人群的1，000多例病例和1，000例代表性对照，我们证明FOXE 1与乳头状甲状腺癌易感性相关。功能分析证明，rs1867277作为一种遗传致病变异体，通过复杂的转录因子网络调节FOXE1的表达。这种方法构成了一个成功的近似定义与个体易感性相关的甲状腺癌风险基因，并确定FOXE 1作为其发展的关键因素。
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 from a 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. Although follicular cell-derived thyroid cancer has an important genetic component, efforts in identifying major susceptibility genes have not been successful. Probably this is due to the complex nature of this disease that involves both genetic and environmental factors, as well as the interaction between them, which could be ultimately modulating the individual susceptibility. In this study, focused on genes carefully selected by their biological relation with the disease, and using more than 1,000 cases and 1,000 representative controls from two independent Caucasian populations, we demonstrate that FOXE1 is associated with Papillary Thyroid Cancer susceptibility. Functional assays prove that rs1867277 behaves as a genetic causal variant that regulates FOXE1 expression through a complex transcription factor network. This approach constitutes a successful approximation to define thyroid cancer risk genes related to individual susceptibility, and identifies FOXE1 as a key factor for its development.
登录
查看更多内容
DOI：
10.1073/pnas.0802682105
发表时间：
2008-05-20
影响因子：
11.1
作者：
Jazdzewski, Krystian;Murray, Elizabeth L.;de la Chapelle, Albert
通讯作者：
de la Chapelle, Albert
影响因子：
6.5
作者：
Eichberger, T;Regl, G;Frischauf, AM
通讯作者：
Frischauf, AM
影响因子：
30.8
作者：
Gudmundsson, Julius;Sulem, Patrick;Gudbjartsson, Daniel F.;Jonasson, Jon G.;Sigurdsson, Asgeir;Bergthorsson, Jon T.;He, Huiling;Blondal, Thorarinn;Geller, Frank;Jakobsdottir, Margret;Magnusdottir, Droplaug N.;Matthiasdottir, Sigurborg;Stacey, Simon N.;Skarphedinsson, Oskar B.;Helgadottir, Hafdis;Li, Wei;Nagy, Rebecca;Aguillo, Esperanza;Faure, Eduardo;Prats, Enrique;Saez, Berta;Martinez, Mariano;Eyjolfsson, Gudmundur I.;Bjornsdottir, Unnur S.;Holm, Hilma;Kristjansson, Kristleifur;Frigge, Michael L.;Kristvinsson, Hoskuldur;Gulcher, Jeffrey R.;Jonsson, Thorvaldur;Rafnar, Thorunn;Hjartarsson, Hannes;Mayordomo, Jose I.;de la Chapelle, Albert;Hrafnkelsson, Jon;Thorsteinsdottir, Unnur;Kong, Augustine;Stefansson, Kari
通讯作者：
Stefansson, Kari
影响因子：
4
作者：
Joyce, Tobias;Cantarella, Daniela;Pintzas, Alexander
通讯作者：
Pintzas, Alexander
影响因子：
20.3
作者：
Barrans, SL;Fenton, JAL;Jack, AS
通讯作者：
Jack, AS