JP5695181B2 - Hcv治療成果を予測する一塩基多型 - Google Patents
Hcv治療成果を予測する一塩基多型 Download PDFInfo
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Description
本発明の理解を容易にするために、多数の用語を以下に定義する。本明細書中で定義する用語は、本発明に関係する分野の当業者が一般に理解している意味をもつ。“a”、“an”および“the”などの用語は、単一のものだけを表わすのではなくその全般的クラスを含むものとし、その特定の例を説明のために採用できる。本明細書中の専門用語は本発明の特定の態様を記述するために用いられるが、それらの使用が特許請求の範囲に示したもの以外に本発明を限定することはない。
患者試料の採集およびウイルス学的エンドポイント
2つの大規模ランダム化多国籍第III相試験に参加した慢性C型肝炎患者サブセットからの試料を分析した3,15。1つの試験では、インターフェロンナイーブ患者を、ペグインターフェロン アルファ−2a(40KD)単剤もしくはリバビリンとの組合わせ、または通常インターフェロン アルファ−2b+リバビリンによる、48週間の治療にランダム化した3。前回のペグインターフェロン アルファ−2b(12KD)+リバビリンの12週間コースに対するノンレスポンダーのみが第2の試験に適格であり、患者を標準または誘導用量計画のいずれかのペグインターフェロン アルファ−2a(40KD)による48または72週間のいずれかの治療にランダム化した(すべての患者に標準用量のリバビリンを投与)15。これらの試験の試験設計、包含および除外の基準、ならびに一次結果は他に公表されている3,15。
EVRについてのGWAS分析において、EVRグループは、インターフェロンナイーブ被験集団からのEVRを伴う遺伝子型−1患者すべてから構成された。非EVRグループは、1)PEG化インターフェロン治療により再攻撃した被験集団からの患者すべて、および2)PEG化インターフェロン+リバビリンで治療した治療ナイーブ被験集団からの遺伝子型−1非EVR患者から構成された。
遺伝子型データ分析
1,016,423のマーカーにつき、Illumina Infinium(登録商標)HD Assay Superで、HumanOmni1 Quad(v1.0)チップおよびiScanスキャナーを用いて、試料を遺伝子型判定した。重複試料間の不一致呼出し(discordant call)、過剰のヘテロ接合性、低い呼出し率(<0.95)、クラスター分離、GenTrainスコア、強度およびクラスター幅についてSNPをゼロ設定するために、初期品質管理を行なった。合計25の試料が品質検査またはその後の遺伝子型判定試験に不合格であった。品質管理後に、遺伝子型呼出しをもつ1,002,139のSNPsが得られた。自己申告による白人集団について、染色体当たりのSNPsの数、対立遺伝子頻度分布、およびHardy Weinberg平衡を計算した。
ウイルス応答(EVRまたはSVR)と基点変数(連続変数として挿入した年齢、肥満指数[BMI]、HCV RNAレベルおよびALT商、カテゴリー変数として挿入した性別、HCV遺伝子型、組織診[肝硬変の有無]および人種)との関連性を、一変量ロジスティック回帰モデルにおいて評価した。
ウイルス応答=BMI + 性別 + 年齢 + HCV RNAレベル + ALT商 + PCA成分
ゼロモデルにおいては、SNPsの遺伝的影響をゼロと仮定した。
ウイルス応答=BMI + 性別 + 年齢 + HCV RNAレベル + ALT商 + PCA成分 + SNP
LRTを用いて、それぞれの対立モデル(すなわち、SNPsを含む)についての最大尤度推定値を対応するゼロモデル(すなわち、SNPsを含まない)と比較した:識別パラメーター数に等しいχ2分布および自由度をもつもの。SNPsを連続変数(0、1、2)としてモデルに挿入した。PCA成分は分析集団の上位5成分に相当していた。同様なモデルを自己申告による白人集団および非遺伝子型1集団において実行した。
合計406人の治療ナイーブ患者、および前回のペグインターフェロン アルファ−2b(12KD)による治療コースに応答しなかった426人の患者について試料を入手した。EVRの分析は800人の患者からのデータに基づき、これにはEVRを達成した363人の個体(45%)およびEVRを達成しなかった437人の個体(55%)が含まれていた。SVRの分析は663人の患者からのデータに基づき、これにはSVRを達成した245人の患者(37%)およびSVRを達成しなかった418人(63%)が含まれていた。EVRおよびSVRの分析に含めた患者の基点特性を表1に示す。
遺伝子型について分析した合計4つの試料を、血縁係数が高い(高い近親度を示す)という理由で除外した。遺伝子型1患者からのデータの分析には、EVR状態が分かっている627人の患者(215人のレスポンダー[34.3%]および412人のノンレスポンダー[65.7%])、およびSVR状態が分かっている516人の患者(128人のレスポンダー[24.8%]および388人のノンレスポンダー[75.2%])が含まれていた。
それぞれSVRおよびEVRに関連する上位6つのSNPsは同一であり、第19染色体のIL−28領域に含まれていた。SVRおよびEVRに関連する上位2つのSNPsは、rs12979860(それぞれ、p=1.4×10−21およびp=5.0×10−26)およびrs12980275(それぞれ、p=5.8×10−18およびp=4.9×10−23)であった。SVRに関連する残り6つのSNPs(表2)のうち、EVRに関連するものはなく、第19染色体上に位置するものはなく、4つ(rs943897、rs17671102、rs4961441およびrs1892723)は稀なホモ接合体クラスにおける少数の観察(BB<10人の個体)であるので、偽関連の可能性がある。EVRに関連する残り13のSNPs(表2)のうち、SVRに関連するものはなく、1つだけ(rs4803223)が第19染色体上に位置し、2つ(rs1189800およびrs4975629)は偽関連の可能性がある。
IL28B間の関連性をより良く解明および理解するために、まず自己申告による白人集団における非遺伝子型1中のrs12979860間の関連性を探査する。GWASの場合と同じロジスティック回帰モデルで、SVRとrs12979860 C対立遺伝子番号の間に、名目上の第1種過誤5%で境界線上の有意な関連性がみられる(OR=1.88,95% CI=[0.97;3.67],p=0.06)。同様に、EVRとrs12979860 C対立遺伝子番号の間に有意の関連性がみられる(OR=2.27,95% CI[1.12;4.70],p=0.02)。
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Claims (3)
- HCVに感染しているヒト対象のインターフェロン治療に対する持続的ウイルス応答を予測するための方法であって、
そのヒト対象からの試料を用意し、第4染色体における一塩基多型の存在を検出し、一塩基多型が存在すればその対象はインターフェロン治療に対する持続的ウイルス応答の可能性が高いと判定し、その際、一塩基多型がrs10009948におけるG、rs10023606におけるG、およびrs7673763におけるTからなる群から選択される方法。 - 対象が遺伝子型−1 HCVに感染している、請求項1に記載の方法。
- インターフェロン治療が、ペグインターフェロン アルファ−2a単剤療法、ペグインターフェロン アルファ−2aとリバビリン、またはインターフェロン アルファ−2bとリバビリンからなる群から選択される治療を含む、請求項1または2に記載の方法。
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