Polymorphic length of FOXE1 alanine stretch:: evidence for genetic susceptibility to thyroid dysgenesis
Polymorphic length of FOXE1 alanine stretch:: evidence for genetic susceptibility to thyroid dysgenesis
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DOI：
10.1007/s00439-007-0420-5
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发表时间：
2007-12-01
期刊：
影响因子：
5.3
通讯作者：
Polak, Michel
中科院分区：
文献类型：
--
作者：
Carre, Aurore;Castanet, Mireille;Polak, Michel
甲状腺发育不全（TD）（OMIM 218700）引起的先天性甲状腺功能减退症的家族性病例发生频率比偶然发生的高15倍，FOXE 1是这种遗传易感性的候选基因之一，并含有丙氨酸束。我们的目的是评估FOXE 1丙氨酸段长度对TD遗传易感性的影响。进行了病例对照关联研究（基于115例TD患者和129例对照，通过直接测序进行基因分型）和传递不平衡检验（TDT）分析。还研究了含有14或16个丙氨酸的FOXE 1构建体的转录活性。在病例对照关联研究中，16/16和16/14基因型与TD呈负相关（OR = 0.39，95%CI = 0.22-0.68，P = 0.0005），强烈提示道中16种丙氨酸的存在保护TD的发生。在异位甲状腺患者亚组中，这种相关性更强（OR = 0.28，95%CI = 0.13-0.58，P = 0.00015）。在39个三组中进行的TDT分析证实了保护作用（x（2）2 = 4.3，P = 0.0374）。另外，14/14基因型的存在与TD的风险增加相关（OR = 2.59，95%CI = 1.56-4.62，P = 0.0005）。表达研究表明，含16个丙氨酸的FOXE 1的转录活性显著高于含14个丙氨酸的FOXE 1（P < 0.003），而蛋白质的核定位不受影响。我们得出结论，FOXE 1通过其含有丙氨酸的延伸显著调节TD发生的风险，增强了含有丙氨酸的转录因子与疾病的联系机制。
Familial cases of congenital hypothyroidism from thyroid dysgenesis (TD) (OMIM 218700) occur with a frequency 15-fold higher than by chance, FOXE1 is one of the candidate genes for this genetic predisposition and contains an alanine tract. Our purpose is to assess the influence of length of the alanine tract of FOXE1 on genetic susceptibility to TD. A case-control association study (based on 115 patients affected by TD and 129 controls genotyped by direct sequencing) and transmission disequilibrium testing (TDT) analyses were performed. The transcriptional activities of FOXE1 constructs containing 14 or 16 alanines were also studied. In the case-control association study, the 16/16 and 16/14 genotypes were inversely associated with TD (OR = 0.39, 95% CI = 0.22-0.68, P = 0.0005), strongly suggesting that the presence of 16 alanines in the tract protect against the occurrence of TD. This association was stronger in the subgroup of patients with ectopic thyroid (OR = 0.28, 95% CI = 0.13-0.58, P = 0.00015). The protection was confirmed by the TDT analysis performed in 39 trios (x(2) 2 = 4.3, P = 0.0374). Alternatively, the presence of the 14/14 genotype is associated with an increase risk of TD (OR = 2.59, 95% CI = 1.56-4.62, P = 0.0005). The expression studies showed that the transcriptional activities of FOXE1 with 16 alanines were significantly higher (1.55-fold) than FOXE1 containing 14 alanines (P < 0.003), while the nuclear localisation of the proteins was not affected. We conclude that FOXE1 through its alanine containing stretch modulates significantly the risk of TD occurrence, enhancing a mechanism linking an alanine containing transcription factor to disease.