Genotype Analyses in the Japanese and Belarusian Populations Reveal Independent Effects of rs965513 and rs1867277 but Do Not Support the Role of FOXE1 Polyalanine Tract Length in Conferring Risk for Papillary Thyroid Carcinoma.
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.



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.



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.



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.
1 Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .
Alyaksandr V
AV
Nikitski
1 Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .
Tatiana I
TI
Rogounovitch
1 Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .
Andrey
A
Bychkov
2 Center for the Promotion of Interdisciplinary Education and Research, Kyoto University , Kyoto, Japan .
Meiko
M
Takahashi
3 Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .
Koh-Ichiro
KI
Yoshiura
1 Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .|4 Nagasaki University Research Center for Genomic Instability and Carcinogenesis , Nagasaki, Japan .
Norisato
N
Mitsutake
5 Center for Genomic Medicine, Kyoto University Graduate School of Medicine , Kyoto, Japan .
Takahisa
T
Kawaguchi
1 Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .
Michiko
M
Matsuse
6 Department of Endocrinology, Belarusian Academy for Postgraduate Education , Minsk, Belarus .
Valentina M
VM
Drozd
7 Department of Oncology, Belarusian Academy for Postgraduate Education , Minsk, Belarus .
Yuri
Y
Demidchik
8 Kuma Hospital , Kobe, Japan .
Eijun
E
Nishihara
8 Kuma Hospital , Kobe, Japan .
Mitsuyoshi
M
Hirokawa
8 Kuma Hospital , Kobe, Japan .
Akira
A
Miyauchi
9 Ecological Genetics Laboratory, Vavilov Institute of General Genetics, Russian Academy of Sciences , Moscow, Russia .|10 Department of Radiation Molecular Epidemiology, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .
Alexander V
AV
Rubanovich
5 Center for Genomic Medicine, Kyoto University Graduate School of Medicine , Kyoto, Japan .
Fumihiko
F
Matsuda
1 Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .|10 Department of Radiation Molecular Epidemiology, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .
Shunichi
S
Yamashita
10 Department of Radiation Molecular Epidemiology, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki, Japan .
Vladimir A
VA
Saenko
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D044466:Asian People / Q000235:genetics; D002291:Carcinoma, Papillary / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D002094:Republic of Belarus; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D010455:Peptides; C019529:polyalanine
FOXE1 polymorphism; case-control association study; functional analysis of transactivation potential; genotype; papillary thyroid carcinoma