自己免疫性甲状腺疾患(橋本病)の疾患感受性遺伝子の同定とその機能解析

• 研究課題/領域番号: 12307056
• 研究種目: 基盤研究(A)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 人類遺伝学
• 研究機関: 国立国際医療センター(研究所) (2001-2003); 九州大学 (2000)
• 研究代表者: 白澤 専二 国立国際医療センター(研究所), 部長 (10253535)
• 研究分担者: 笹月 健彦 国立国際医療センター(研究所), 所長 (50014121) ; 原田 晴仁 国立国際医療センター(研究所), 室長 (00271429) ; 山本 健 九州大学, 生体防御医学研究所, 助教授 (60274528)
• 研究期間 (年度): 2000 – 2003
• 研究課題ステータス: 完了 (2003年度)
• 配分額: 37,730千円 (直接経費: 31,700千円、間接経費: 6,030千円); 2003年度: 7,410千円 (直接経費: 5,700千円、間接経費: 1,710千円); 2002年度: 9,360千円 (直接経費: 7,200千円、間接経費: 2,160千円); 2001年度: 9,360千円 (直接経費: 7,200千円、間接経費: 2,160千円); 2000年度: 11,600千円 (直接経費: 11,600千円)
• キーワード: 自己免疫性甲状腺疾患 / 疾患感受性遺伝子 / マイクロサテライトマーカー / SNPs / 罹患同胞対 / 連鎖解析 / 相関解析 / アンチセンスRNA / ZFAT / B細胞 / Graves病 / 橋本病 / 罹患同胞対法 / SNP / 自己免疫疾患 / 甲状腺

研究概要

罹患同胞対法による連鎖解析により自己免疫性甲状腺疾患(autoimmune thyroid disease : AITD)感受性遺伝子領域として、8q23-q24および5q31-q33を同定した。8q23-q24領域をマイクロサテライトマーカー、SNPsを用いた患者対照群による相関解析および連鎖不平衡解析により、60kbまで限局化させた。限局化された60kbの遺伝子構造解析を行った結果、有意な相関を示すSNPsが存在する遺伝子として、18個のzinc-fingerドメインを持つ1243個のアミノ酸からなるZinc-finger gene in AITD-susceptibility region(ZFAT)を同定した。ZFATには複数のsplicing variantsが存在し、特にエクソン9abを利用するものは、846アミノ酸からなるtruncated formである(TR-ZFAT)。最も有意な相関を示したSNP(Ex9b-SNP10)はZFATのイントロン9,TR-ZEATの3'UTR,および2個のエクソンよりなる939-ntのnon-coding RNAと考えられるSAS-ZFATのプロモーター領域に位置した。SAS-ZFATはB細胞に強く発現し、Ex9b-SNP10のT-alleleとその発現が末梢血B細胞において逆相関し、一方、TR-ZFATの発現と正に相関した。ゲルシフト解析、レポーター解析によりExgb-SNP10のT-alleleには転写抑制蛋白が結合することが示唆された。更に、SAS-ZFATの発現がTR-ZFATの発現をin vitroで抑制した。これらのことより、B細胞においてExgb-SNP10はSAS-ZFATの発現を制御し、その発現がTR-ZFATの発現を制御することにより、AITDの発症に関与することが示唆された。

研究成果

• [雑誌論文] Association of the T-cell regulatory gene CTLA4 with Graves' disease and autoimmune thyroid disease in the Japanese. (2004)
  • 著者名/発表者名: Furugaki K et al.
  • 雑誌名: Journal of Human Genetics 49 ページ: 166-168
  • 説明: 「研究成果報告書概要(和文)」より
• [雑誌論文] Association of the T-cell regulatory gene CTLA4 with pressGraves' disease and autoimmune thyroid disease in the Japanese. (2004)
  • 著者名/発表者名: Furugaki, K., et al.
  • 雑誌名: Journal of Human Genetics 49 ページ: 166-168
  • 説明: 「研究成果報告書概要(欧文)」より
• [雑誌論文] 自己免疫性甲状腺疾患感受性遺伝子の解明 (2003)
  • 著者名/発表者名: 白澤 専二
  • 雑誌名: 最新医学 58 ページ: 1649-1656
  • 説明: 「研究成果報告書概要(和文)」より
• [雑誌論文] 自己免疫性甲状腺疾患感受性遺伝子の解明AITS-1遺伝子の同定 (2003)
  • 著者名/発表者名: 白澤 専二
  • 雑誌名: 実験医学 21 ページ: 25-29
  • 説明: 「研究成果報告書概要(和文)」より
• [雑誌論文] 自己免疫性甲状腺疾患のゲノム解析 (2002)
  • 著者名/発表者名: 白澤 専二
  • 雑誌名: 医学のあゆみ 202 ページ: 827-832
  • 説明: 「研究成果報告書概要(和文)」より
• [雑誌論文] 自己免疫性甲状腺疾患とゲノム (2002)
  • 著者名/発表者名: 白澤 専二
  • 雑誌名: ゲノム医学 2 ページ: 149-157
  • 説明: 「研究成果報告書概要(和文)」より
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  • 著者名/発表者名: Sakai K et al.
  • 雑誌名: Human Molecular Genetics 10 ページ: 1379-1386
  • 説明: 「研究成果報告書概要(和文)」より
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  • 著者名/発表者名: Sakai, K., et al.
  • 雑誌名: Human Molecular Genetics 10 ページ: 1379-1386
  • 説明: 「研究成果報告書概要(欧文)」より
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