The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl

Meiko Takahashi, Vladimir A. Saenko, Tatiana I. Rogounovitch, Takahisa Kawaguchi, Valentina M. Drozd, Hisako Takigawa-Imamura, Natallia M. Akulevich, Chanavee Ratanajaraya, Norisato Mitsutake, Noboru Takamura, Larisa I. Danilova, Maxim L. Lushchik, Yuri E. Demidchik, Simon Heath, Ryo Yamada, Mark Lathrop, Fumihiko Matsuda, Shunichi Yamashita

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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 × 10-9 to 4.9 × 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 × 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.

Original languageEnglish
Article numberddq123
Pages (from-to)2516-2523
Number of pages8
JournalHuman molecular genetics
Volume19
Issue number12
DOIs
Publication statusPublished - Jun 15 2010

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Takahashi, M., Saenko, V. A., Rogounovitch, T. I., Kawaguchi, T., Drozd, V. M., Takigawa-Imamura, H., Akulevich, N. M., Ratanajaraya, C., Mitsutake, N., Takamura, N., Danilova, L. I., Lushchik, M. L., Demidchik, Y. E., Heath, S., Yamada, R., Lathrop, M., Matsuda, F., & Yamashita, S. (2010). The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. Human molecular genetics, 19(12), 2516-2523. [ddq123]. https://doi.org/10.1093/hmg/ddq123