title: The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl.
abstract: Papillary thyroid cancer (PTC) among individuals exposed to radioactive iodine in their childhood or adolescence is a major internationally recognized health consequence of the Chernobyl accident. To identify genetic determinants affecting individual susceptibility to radiation-related PTC, we conducted a genome-wide association study employing Belarusian patients with PTC aged 0-18 years at the time of accident and age-matched Belarusian control subjects. Two series of genome scans were performed using independent sample sets, and association with radiation-related PTC was evaluated. Meta-analysis by the Mantel-Haenszel method combining the two studies identified four SNPs at chromosome 9q22.33 showing significant associations with the disease (Mantel-Haenszel P: mhp = 1.7 x 10(-9) to 4.9 x 10(-9)). The association was further reinforced by a validation analysis using one of these SNP markers, rs965513, with a new set of samples (overall mhp = 4.8 x 10(-12), OR = 1.65, 95% CI: 1.43-1.91). Rs965513 is located 57-kb upstream to FOXE1, a thyroid-specific transcription factor with pivotal roles in thyroid morphogenesis and was recently reported as the strongest genetic risk marker of sporadic PTC in European populations. Of interest, no association was obtained between radiation-related PTC and rs944289 (mhp = 0.17) at 14p13.3 which showed the second strongest association with sporadic PTC in Europeans. These results show that the complex pathway underlying the pathogenesis may be partly shared by the two etiological forms of PTC, but their genetic components do not completely overlap each other, suggesting the presence of other unknown etiology-specific genetic determinants in radiation-related PTC.
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
authors.forename: Meiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Saenko
authors.forename: Tatiana I
authors.initials: TI
authors.lastname: Rogounovitch
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Valentina M
authors.initials: VM
authors.lastname: Drozd
authors.forename: Hisako
authors.initials: H
authors.lastname: Takigawa-Imamura
authors.forename: Natallia M
authors.initials: NM
authors.lastname: Akulevich
authors.forename: Chanavee
authors.initials: C
authors.lastname: Ratanajaraya
authors.forename: Norisato
authors.initials: N
authors.lastname: Mitsutake
authors.forename: Noboru
authors.initials: N
authors.lastname: Takamura
authors.forename: Larisa I
authors.initials: LI
authors.lastname: Danilova
authors.forename: Maxim L
authors.initials: ML
authors.lastname: Lushchik
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Demidchik
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Shunichi
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D000328:Adult; D002291:Carcinoma, Papillary / Q000235:genetics*; D047852:Chernobyl Nuclear Accident; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D056426:Genetic Loci; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*; D055815:Young Adult
chemical_list: C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D005819:Genetic Markers