JP2023021471A - 脳梗塞発症リスク予測方法 - Google Patents
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Abstract
Description
(1) 脳梗塞未発症の被検者由来のサンプルにおけるRNF213 p.R4810K遺伝子多型の有無を検出する検出ステップと、
前記検出ステップにおける前記RNF213 p.R4810K遺伝子多型の有無と、前記被験者の性別情報とに基づいて、当該被験者の脳梗塞発症確率が高いか否かを判定する判定ステップと、
を含む、脳梗塞未発症の被検者の脳梗塞発症リスクを予測する方法。
T又はCである第4766位のSNP(4766 T>C)、
G又はAである第120764位のSNP(120764 G>A)、
G又はAである第152917位のSNP(152917 G>A)、及び
G又はAである第232102位のSNP(232102 G>A)も存在し得る。
脳卒中死亡率は過去数十年間で減少している1)が、脳卒中は世界的に見ても、早期死亡の第2の主要原因であり、身体障害の主要原因でもある2)。世界人口の31%を占める東南アジアおよび東アジアでは、脳卒中が早期死亡の主要原因であり、脳卒中の発生率および罹患率は着実に増加している1,2)。疫学的研究は、脳卒中サブタイプの実質的な地理的差異および人種的差異を示唆している3,4)。心筋塞栓症は西欧諸国の虚血性脳卒中の一般的な病因学的サブタイプである5)。一方、頭蓋内動脈狭窄に起因する大動脈アテローム性動脈硬化症は、ほとんどのアジア諸国において主な病因である6)。環境リスク要因と遺伝的背景の違いが、アジアにおける大動脈アテローム性動脈硬化症の高い罹患率の主な理由であると考えられている。最近、大規模な多祖先ゲノムワイド関連メタアナリシスによって、脳卒中および脳卒中サブタイプに関連する32遺伝子座が同定された7)。この研究では、約800万の一塩基多型(SNPs)が検査された。しかし、この分析は、0.01未満(<0.01)のマイナーアレル頻度(minor-allele frequency;MAF)および虚血性脳卒中のアジア特異的な遺伝的決定因子が未知のままである、領域特異的な希少アレルを除外した。
(研究デザインと参加者)
症例対照研究では、すべての患者の広範な臨床データおよび放射線データを含む国立循環器病研究センター(NCVC)の病院ベースの単一の集団(NCVCバイオバンク)を使用した。書面による同意がすべての試験参加者から得られ、この研究は国立循環器病研究センター(NCVC)の倫理委員会によって承認された。
本研究の参加者は、大阪、関西地区の脳卒中および心血管疾患専門の600床の第三次センターである国立循環器病研究センター(NCVC)で募集された。2012年6月から2017年5月に入院し、NCVCで包括的同意書に署名した非心原性脳塞栓症(大動脈アテローム性動脈硬化症(large-artery atherosclerosis)、小血管閉塞症(small-vessel occlusion)など)の日本人患者383例を本研究に含めた 。日本の厚生労働省のモヤモヤ病研究委員会の基準に基づき、心原性脳塞栓症cardioembolic stroke、確定的/おそらくモヤモヤ病と診断された患者は除外した17)。患者選択手順の流れ図は図1に詳述されている。
連続変数は平均±SDとして表し、スチューデントのt検定(Student’s t-test)を用いて比較した。カテゴリー変数は、数値とパーセンテージとして表現され、カイ2乗検定(chi-square test)と両側検定のフィッシャー正確検定(two-tailed Fisher’s exact test)を適宜用いて比較した。本発明者らは、RNF213多型と虚血性脳卒中のリスクとの間の関連性を、ホモ接合体の数が不十分であるために本研究で優性モデルと仮定して試験した。本発明者らはまた、帰属法(imputation methods)を用いた検証研究(replication studies)と比較するために、メタアナリシスのためのロジスティック加法モデル(log-additive model)の下での関連性を調べた。複数のロジスティック回帰モデル(logistic regression model)を用いて、潜在的な交絡因子を同時に制御した後、各脳卒中サブタイプについてオッズ比(OR Ratio)および95%信頼区間(95%CI)を計算した。モデルで考慮された変数は、年齢(連続)、性別、高血圧、脂質異常血症、糖尿病および喫煙であった。全ての分析は、JMP Pro 12.2ソフトウェア(SAS Institute Inc., Cary、NC)を用いて行った。
本研究では、特に非心原性脳塞栓症脳卒中患者が登録された。上記包括的基準を満たした1,775人の非心原性脳塞栓症脳卒中患者のうち383人(21.6%)がNCVCバイオバンクに参加することに合意し、本研究で分析した。NCVCバイオバンクの参加者と非参加者の両方の患者の特徴は表1に示されている。また、本研究参加者のベースライン特性を表1に示す。
RNF213はもやもや病の感受性遺伝子として同定され、RNF213 p.R4810K多型は日本人のもやもや病患者の90%以上が保有する。RNF213は、血管内皮機能の調整や血管新生に重要な役割を演じていると考えられているが、もやもや病のような特異的な血管障害を引き起こす機序については十分に解明されていない。一方、最近、日本を含むアジアの健常成人でも2-3%にこの遺伝子多型が認められ、もやもや病と診断されていない頭蓋内動脈狭窄患者では20-25%が同様にこの遺伝子多型を保有することが報告されている。もやもや病以外の脳血管障害においてもこの遺伝子多型がリスク因子となり得ることが示唆されている。
本研究は国立循環器病研究センター(NCVC)のバイオバンク登録患者を対象とした単一施設横断研究である。頭蓋内動脈狭窄(Intracranial Arterial Stenosis)を有し20歳以上60歳未満の非心原性脳梗塞(non-cardioembolic stroke)もしくは一過性脳虚血発作(TIA:transient ischemic attacks)を発症した登録患者70名を全て対象とした。心原性脳塞栓症(cardioembolic stroke)およびもやもや病(moyamoya disease)と診断された症例は除外した。書面による同意がすべての対象者から得られ、この研究は国立循環器病研究センター(NCVC)の倫理委員会によって承認された。
対象者の選択基準は以下のとおりであった。
[1] 国立循環器病研究センター(NCVC)のバイオバンク事業に同意した患者。
[2] 20歳以上60歳未満で虚血性脳卒中もしくは一過性脳虚血発作を発症した患者。
[3] 以下の頭蓋内動脈の少なくとも1ヶ所に50%(直径)以上の狭窄もしくは閉塞を有する患者。
中大脳動脈(middle cerebral artery)M1-2 segment、
前大脳動脈(anterior cerebral artery)A1-2 segment、
後大脳動脈(posterior circulation stenosis)P1-2 segment、
脳底動脈。
心原性脳塞栓症の患者、
もやもや病の患者。
脳梗塞病サブタイプは、急性脳卒中治療についてのOrg 10172基準[the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria]に従って分類された。
RNF213 p.R4810K多型の有無と、動脈硬化危険因子、もやもや病の家族歴、及び頭蓋内狭窄の特徴を比較した。
静脈血液サンプルをDNAサンプルとして用いて、DNAサンプルを匿名化した上で京都大学大学院環境衛生学分野にて、TaqMan SNP Assays(Applied Biosystems、Foster City、CA)および7300/7500 Real-Time PCR System(Applied Biosystems、Foster City、CA)を用いてp.R4810Kの遺伝子型決定を行った。
連続変数は平均±SDとして表し、スチューデントのt検定(Student’s t-test)を用いて比較した。カテゴリー変数は、数値とパーセンテージとして表現され、カイ2乗検定(chi-square test)と両側検定のフィッシャー正確検定(two-tailed Fisher’s exact test)を用いて比較した。各脳卒中サブタイプについてオッズ比(OR Ratio)および95%信頼区間(95%CI)を計算した。モデルで考慮された変数は、年齢(連続)、性別、高血圧、脂質異常血症、2型糖尿病、及び喫煙習慣であった。全ての分析は、JMP version 11.2.0 ソフトウェア(SAS Institute Inc., Cary、NC)を用いて行った。確率値は両側であり、p<0.05は有意であると考えられた。
全70名の患者背景とRNF213 p.R4810K多型との関連を表5に示す。表5において、カテゴリ変数は、患者数(%)で示す。RNF213 p.R4810K多型キャリア患者17名の特徴を表6に示す。
Bil; bilateral
Rt; right
Lt; left
UE; undetermined etiology
LAA; large artery atherosclerosis
本研究は、前方循環系の脳動脈狭窄、特にM1もしくはA1狭窄を有する患者においてRNF213 p.R4810K多型の保有率が高いことを示した。高齢者と比較して血管リスクが少ない若年患者において高いp.R4810K多型保有率を認め、p.R4810K多型が脳梗塞発症と関連する可能性がある。また、頭蓋内前方・後方循環、遠位部の狭窄まで対象とした本研究において、M1/A1狭窄を有する患者に多く本遺伝子多型を認め、本遺伝子多型と、頭蓋内狭窄部位との関連が明らかとなった。
上記のことから、RNF213 p.R4810K多型は、前方循環系の脳動脈狭窄、特にM1もしくはA1狭窄を伴う若年発症非心原性脳梗塞患者と相関を有することがわかる。
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Claims (2)
- 脳梗塞未発症の被検者由来のサンプルにおけるRNF213 p.R4810K遺伝子多型の有無を検出する検出ステップと、
前記検出ステップにおける前記RNF213 p.R4810K遺伝子多型の有無と、前記被験者の性別情報と、に基づいて当該被験者の脳梗塞発症確率が高いか否かを判定する判定ステップと、
を含み、
前記検出ステップにおいて、前記RNF213 p.R4810K遺伝子多型が検出された場合、前記判定ステップにおいて、当該被験者の性別が女性の場合には、前記RNF213 p.R4810K遺伝子多型を有する当該女性被験者は、前記RNF213 p.R4810K遺伝子多型を有しない者に比べて、頭蓋内前方循環動脈狭窄によるアテローム血栓性脳梗塞発症のリスクが高いと判定する、脳梗塞発症リスクを予測する方法。 - 脳梗塞未発症の被検者由来のサンプルにおけるRNF213 p.R4810K遺伝子多型の有無を検出する検出ステップと、
前記検出ステップにおける前記RNF213 p.R4810K遺伝子多型の有無と、前記被験者の性別情報と、に基づいて当該被験者の脳梗塞発症確率が高いか否かを判定する判定ステップと、
を含み、
前記検出ステップにおいて、前記RNF213 p.R4810K遺伝子多型が検出された場合、前記判定ステップにおいて、当該被験者の性別が女性の場合には、前記RNF213 p.R4810K遺伝子多型を有する当該女性被験者は、前記RNF213 p.R4810K遺伝子多型を有する男性の場合に比べて、頭蓋内前方循環動脈狭窄によるアテローム血栓性脳梗塞発症のリスクがより高いと判定する、脳梗塞発症リスクを予測する方法。
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