Alyaksandr V Nikitski1, Tatiana I Rogounovitch1, Andrey Bychkov1, Meiko Takahashi2, Koh-Ichiro Yoshiura3, Norisato Mitsutake1,4, Takahisa Kawaguchi5, Michiko Matsuse1, Valentina M Drozd6, Yuri Demidchik7, Eijun Nishihara8, Mitsuyoshi Hirokawa8, Akira Miyauchi8, Alexander V Rubanovich9,10, Fumihiko Matsuda5, Shunichi Yamashita1,10, Vladimir A Saenko10. 1. 1 Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan . 2. 2 Center for the Promotion of Interdisciplinary Education and Research, Kyoto University , Kyoto, Japan . 3. 3 Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan . 4. 4 Nagasaki University Research Center for Genomic Instability and Carcinogenesis , Nagasaki, Japan . 5. 5 Center for Genomic Medicine, Kyoto University Graduate School of Medicine , Kyoto, Japan . 6. 6 Department of Endocrinology, Belarusian Academy for Postgraduate Education , Minsk, Belarus . 7. 7 Department of Oncology, Belarusian Academy for Postgraduate Education , Minsk, Belarus . 8. 8 Kuma Hospital , Kobe, Japan . 9. 9 Ecological Genetics Laboratory, Vavilov Institute of General Genetics, Russian Academy of Sciences , Moscow, Russia . 10. 10 Department of Radiation Molecular Epidemiology, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .
Abstract
BACKGROUND: Several functional single-nucleotide polymorphisms (SNPs) at the FOXE1 locus on chromosome 9q22.33 have been associated with the risk for papillary thyroid carcinoma (PTC). This study set out to elucidate whether their effects are independent, using genotyping results in populations of Asian and European descent. METHODS: SNPs rs965513 and rs1867277 and a polymorphic region determining the length of the FOXE1 polyalanine (poly-Ala) tract were genotyped in 501 patients with PTC and 748 healthy individuals from Japan, and in 660 patients and 820 population controls from Belarus. Functional analysis of transactivation activities of FOXE1 isoforms with varying number of alanine repeats was performed by a Dual-Luciferase® Assay. RESULTS: All three polymorphisms were significantly associated with PTC in both populations on univariate analysis. However, conditional analysis revealed independent effects of rs965513 and rs1867277 SNPs but not of the FOXE1 poly-Ala polymorphism. The independent effect of the lead rs965513 SNP was observed in both populations, while that of rs1867277 was only identified in the Japanese population, in which linkage disequilibrium between the three polymorphisms is markedly weaker. Despite the strong decrease in transcriptional activity with increasing FOXE1 poly-Ala tract length, no difference in transactivation potential of the FOXE1 poly-Ala isoforms could be seen after adjustment for the minimal promoter activity in the reporter vectors. Plasmids encoding FOXE1 isoforms of increasing poly-Ala tract length were also found to produce less FOXE1 protein after cell transfection. CONCLUSIONS: The functional variants rs965513 and rs1867277 independently contribute to genetic predisposition to PTC, while a contributing role of the FOXE1 poly-Ala polymorphism could not be confirmed.
BACKGROUND: Several functional single-nucleotide polymorphisms (SNPs) at the FOXE1 locus on chromosome 9q22.33 have been associated with the risk for papillary thyroid carcinoma (PTC). This study set out to elucidate whether their effects are independent, using genotyping results in populations of Asian and European descent. METHODS: SNPs rs965513 and rs1867277 and a polymorphic region determining the length of the FOXE1polyalanine (poly-Ala) tract were genotyped in 501 patients with PTC and 748 healthy individuals from Japan, and in 660 patients and 820 population controls from Belarus. Functional analysis of transactivation activities of FOXE1 isoforms with varying number of alanine repeats was performed by a Dual-Luciferase® Assay. RESULTS: All three polymorphisms were significantly associated with PTC in both populations on univariate analysis. However, conditional analysis revealed independent effects of rs965513 and rs1867277 SNPs but not of the FOXE1poly-Ala polymorphism. The independent effect of the lead rs965513 SNP was observed in both populations, while that of rs1867277 was only identified in the Japanese population, in which linkage disequilibrium between the three polymorphisms is markedly weaker. Despite the strong decrease in transcriptional activity with increasing FOXE1poly-Ala tract length, no difference in transactivation potential of the FOXE1poly-Ala isoforms could be seen after adjustment for the minimal promoter activity in the reporter vectors. Plasmids encoding FOXE1 isoforms of increasing poly-Ala tract length were also found to produce less FOXE1 protein after cell transfection. CONCLUSIONS: The functional variants rs965513 and rs1867277 independently contribute to genetic predisposition to PTC, while a contributing role of the FOXE1poly-Ala polymorphism could not be confirmed.
Entities:
Keywords:
FOXE1 polymorphism; case-control association study; functional analysis of transactivation potential; genotype; papillary thyroid carcinoma
Authors: María Sánchez-Ares; Soledad Cameselle-García; Ihab Abdulkader-Nallib; Gemma Rodríguez-Carnero; Carolina Beiras-Sarasquete; José Antonio Puñal-Rodríguez; José Manuel Cameselle-Teijeiro Journal: Front Endocrinol (Lausanne) Date: 2022-02-28 Impact factor: 5.555