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脊柱後縦靱帯骨化症の遺伝学的研究

小池, 良直 北海道大学

2023.06.30

概要

【背景、目的】
脊柱後縦靭帯骨化症 (ossification of the posterior longitudinal ligament of the
spine : OPLL)は椎体後面を縦走する後縦靱帯が骨化することで脊柱管の狭窄を
きたし、重篤な運動・感覚障害を生じる難病である。症状が重度な進行例に対し
ては、脊髄の除圧目的の手術が選択されるが、根本的な治療方法は無く、予防法
すら確立されていない。
治療・予防法の確立のためには病因を明らかにする必要がある。OPLL は遺伝
的要因と環境要因が複雑に組み合わさることで発症する多因子遺伝疾患と推定
されている。OPLL の遺伝的要因を明らかにするため、過去に全ゲノム相関解析
(genome-wide association study: GWAS)が行われ 6 つの疾患感受性領域が発見され
た。その後の機能解析により、8q23.1 の領域に存在する疾患感受性遺伝子 RSPO2
の OPLL への関与が示された。OPLL の病因の一端が明らかにされたが、この領
域のみでは OPLL の病因の一部しか説明できないことから、依然として多くの
遺伝的要因が OPLL に関与していると推測されている。
また、OPLL は 2 型糖尿病 (type 2 diabetes: T2D)、肥満度 (body mass index: BMI)
など他の形質との関連が複数報告されている。特に T2D に関しては多くの報告
がなされている。これらの関連は OPLL の病因を紐解く鍵となりうるが、肝心
な OPLL との「因果関係」は示されていない。
本研究は、規模を拡大した GWAS を行うことで、OPLL の治療につながる新
規疾患感受性領域を同定すること、さらには遺伝統計学的な切り口から OPLL の
治療法、予防法につながる新知見を得ることを目的とした。
【方法】
異なる時期に募集した 3 つのコホートの計 2,010 人の OPLL 患者を含む日本
人 22,016 人を対象として世界最大規模の OPLL GWAS メタ解析を行った。末梢
血から DNA を抽出し、ジェノタイピング後にデータの処理 (quality control)を行
い、各コホートで GWAS を行った。その後、メタ解析でコホートデータを統合
し、ゲノム上の疾患感受性領域を同定した。さらに、罹患部位により OPLL を頚
椎 (cervical: C)、胸椎 (thoracic: T)-OPLL に分類し、このサブタイプでの GWAS
解析(サブ解析)を行った。さらに、GWAS 解析結果を使用し、Gene-based 相
関解析、Summary-based Mendelian randomization (SMR)を行い、さらなる OPLL 関
連遺伝子を検索した。
次に、GWAS データと既報の日本人 96 形質の GWAS 要約統計量を用い、OPLL
とこれらの形質との遺伝相関 (genetic correlation: GC)を算出した。 ...

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