JP6449235B2 - 治療に対する応答性を予測するための遺伝マーカー - Google Patents
治療に対する応答性を予測するための遺伝マーカー Download PDFInfo
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- JP6449235B2 JP6449235B2 JP2016504603A JP2016504603A JP6449235B2 JP 6449235 B2 JP6449235 B2 JP 6449235B2 JP 2016504603 A JP2016504603 A JP 2016504603A JP 2016504603 A JP2016504603 A JP 2016504603A JP 6449235 B2 JP6449235 B2 JP 6449235B2
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- 125000006626 methoxycarbonylamino group Chemical group 0.000 description 1
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- 238000007069 methylation reaction Methods 0.000 description 1
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- IWXXJNAJZFNRLB-UHFFFAOYSA-N n-(2-sulfanylphenyl)cyclohexanecarboxamide Chemical compound SC1=CC=CC=C1NC(=O)C1CCCCC1 IWXXJNAJZFNRLB-UHFFFAOYSA-N 0.000 description 1
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- 229940089484 pravachol Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
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- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6844—Nucleic acid amplification reactions
- C12Q1/686—Polymerase chain reaction [PCR]
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6869—Methods for sequencing
- C12Q1/6874—Methods for sequencing involving nucleic acid arrays, e.g. sequencing by hybridisation
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
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- C12Q2600/00—Oligonucleotides characterized by their use
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Description
で示される化合物としても公知の((4S,5R)−5−[3,5−ビス(トリフルオロメチル)フェニル]−3−{[4’−フルオロ−2’−メトキシ−5’−(プロパン−2−イル)−4−(トリフルオロメチル)[1,1’−ビフェニル]−2−イル]メチル}−4−メチル−1,3−オキサゾリジン−2−オン)を表す。
で示される化合物としても公知のtrans−4−({(5S)−5−[{[3,5−ビス(トリフルオロメチル)フェニル]メチル}(2−メチル−2H−テトラゾール−5−イル)アミノ]−7,9−ジメチル−2,3,4,5−テトラヒドロ−1H−ベンゾアゼピン−1−イル}メチル)シクロヘキサンカルボン酸を表す。
で示される化合物としても公知の(2R,4S)−4−[(3,5−ビストリフルオロメチルベンジル)メトキシカルボニルアミノ]−2−エチル−6−トリフルオロメチル−3,4−ジヒドロ−2H−キノリン−1−カルボン酸エチルエステルを表す。
で示される化合物としても公知の(5S)−5−キノリノール、4−シクロヘキシル−2−シクロペンチル−3−[(S)−フルオロ[4−(トリフルオロメチル)フェニル]メチル]−5,6,7,8−テトラヒドロ−7,7−ジメチル−を表す。
(a)以下の部位:rs1967309、rs12595857、rs2239310、rs11647828、rs8049452、rs12935810、rs74702385、rs17136707、rs8061182、rs111590482、rs4786454、rs2283497、rs2531967、rs3730119、rs13337675、rs12920508、rs12599911、rs2531971又はrs2238448の1つ以上で応答向上型遺伝子型を有する対象を選択すること;
(b)該対象にHDL上昇剤又はHDL模倣剤、特にCETP阻害薬/モデュレーターを投与すること
を含む方法を提供する。
(a)以下の部位:rs1967309、rs12595857、rs2239310、rs11647828、rs8049452、rs12935810、rs74702385、rs17136707、rs8061182、rs111590482、rs4786454、rs2283497、rs2531967、rs3730119、rs13337675の1つ以上で応答向上型遺伝子型を有する対象を選択すること;
(b)該対象にHDL上昇剤又はHDL模倣剤、特にCETP阻害薬/モデュレーターを投与すること
を含む方法を提供する。
(a)rs1967309で応答向上型多型を有する対象、特にrs1967309でAA遺伝子型を有する対象を選択すること;
(b)該対象にHDL上昇剤又はHDL模倣剤、特にCETP阻害薬/モデュレーターを投与すること
を含む方法を提供する。
(a)以下の部位:rs1967309、rs12595857、rs2239310、rs11647828、rs8049452、rs12935810、rs74702385、rs17136707、rs8061182、rs111590482、rs4786454、rs2283497、rs2531967、rs3730119、rs13337675、rs12920508、rs12599911、rs2531971又はrs2238448の1つ以上で対象を遺伝子型決定すること;
(b)該対象にHDL上昇剤又はHDL模倣剤、特にCETP阻害薬/モデュレーターを投与すること
を含む方法を提供する。
(c)以下の部位:rs1967309、rs12595857、rs2239310、rs11647828、rs8049452、rs12935810、rs74702385、rs17136707、rs8061182、rs111590482、rs4786454、rs2283497、rs2531967、rs3730119、rs13337675の1つ以上で対象を遺伝子型決定すること;
(d)該対象にHDL上昇剤又はHDL模倣剤、特にCETP阻害薬/モデュレーターを投与すること
を含む方法を提供する。
a. rs12595857/GG、rs1967309/AA、rs111590482/AG、rs111590482/GG、rs11647828/GG、rs12935810/GG、rs17136707/GG、rs2239310/GG、rs2283497/AA、rs2531967/AA、rs3730119/AA、rs4786454/AA、rs74702385/GA、rs74702385/AA、rs8049452/GG及びrs8061182/AAからなる群より選択される1つ以上の遺伝マーカーの存在について患者の試料を分析すること、並びに
b. 該遺伝マーカーの1つ以上を保有する患者を、HDL上昇剤又はHDL模倣剤、特にCETP阻害薬/モデュレーターを用いて処置すること
を含む、患者を処置する方法を提供する。
a. 遺伝物質を含む試料を個体から得ること;
b. 試料を試薬と接触させること、試薬と表7より選択される遺伝マーカーとの間で複合体を生成させること;
c. 複合体を検出して、試料に関連するデータセットを得ること、及び
d. データセットを分析して、遺伝マーカーの存在又は不在を決定すること
を含む、HDL上昇薬に対する個体の応答性を決定する方法。
(a)患者由来の試料中からrs1967309でAA遺伝子型を検出すること、
(b)AA遺伝子型を有するrs1967309が患者由来の試料中から検出されるとき、HDL上昇剤又はHDL模倣剤を含む治療に応答する可能性がより高いとして患者を選択すること
を含む方法を提供する。
で示される化合物としても公知のチオイソ酪酸S−(2−{[1−(2−エチル−ブチル)−シクロヘキサンカルボニル]−アミノ}−フェニル)エステルである。
試料中の特定の遺伝子型の同定は、当業者に周知のいくつかの方法のいずれかによって行うことができる。例えば、多型の同定は、アレルをクローニングすること及び当技術分野において周知の技法を使用してそれを配列決定することによって果たすことができる。あるいは、遺伝子配列は、例えばPCRを使用して、ゲノムDNAから増幅することができ、産物が配列決定される。ポリメラーゼ連鎖反応(PCR)、ライゲーション連鎖反応(ligation chain reaction)(LCR)又はライゲーション増幅及び自家持続配列複製法などの増幅法を含む、対象のDNAを単離し、所与の遺伝マーカーについて分析するための多数の方法が当技術分野において公知である。所与の遺伝子ローカスで突然変異について患者のDNAを分析するためのいくつかの非限定的な方法を、下述する。
本明細書に提供される配列は、NCBIデータベースから入手することができ、www.ncbi.nlm.nih.gov/sites/entrez?db=geneから検索することができる。これらの配列は、また、注釈及び改変された配列に関する。本発明は、また、本明細書に提供される簡潔な配列の相同配列及び変異体が使用される技法及び方法を提供する。好ましくは、そのような「変異体」は遺伝子変異体である。NCB1データベースから、ホモサピエンス(homo sapiens)アデニル酸シクラーゼ9型(ACDY9)をコードするヌクレオチド配列が入手可能である。
NCBI参照配列:NCBIアクセッションナンバーNG_011434.1
ホモサピエンス16番染色体ゲノムコンティグ、GRCh37.p10一次アセンブリ
NCBI参照配列:NCBIアクセッションナンバーNT_010393.16
a. rs1967309
1. 1000人ゲノム公的データベースからの位置、r2及びD’値
2. NCBIのdbSNP公的データベース、バージョン137からの参照配列及びHGV名
dal−OUTCOMES試験(NC20971)は、急性冠症候群(ACS)のため最近入院した患者におけるCETP阻害薬ダルセトラピブの安全性及び有効性を評価するための二重盲検ランダム化プラセボ対照並行群間多施設第III相試験であった。中間解析の時点で、該試験は、2つの処置群、すなわちプラセボ(患者7933人)及びダルセトラピブ(1日600mg;患者7938人)に振り分けられた、ランダム化された患者15871人を含んでいた。該試験は、プラセボ群に比べてダルセトラピブ群における主要有効性評価項目でのイベント率の低下の証拠を示さなかった。dal−OUTCOMES試験の詳細は、G. Schwartz et al., N. Engl. J. Med.367;22, 2012から見いだすことができる。遺伝子型決定:
Beaulieu-Saucier Pharmacogenomics Centreで統計解析計画を策定し、最終バージョンが遺伝子型決定完了前の2012年10月に承認された。遺伝子データに行われた統計検定は、両側で行い、SNPの複数の検査を考慮するために調整された。有意な結果についての受容しきい値としてゲノムワイド有意性しきい値p<5・10−8を用いた。p<1・10−6を有する結果を潜在的候補として見なした。集団構造による交絡を回避するために、多変量モデルは、共変量としての性別及び集団構造の最初の5つの主成分(PC)を含んだ。解析対象集団をダルセトラピブ処置群への参加者として定義し、効果の不在を確認するため、及び合わせた集団で遺伝子−処置群相互作用について検定するためにプラセボ群での妥当性確認を行った。
のように共変量に関して調製し、相加的検定下の帰無仮説(null)(H0)はb1=0である。最初に、イベントの不発生に対する発生について、PLINKソフトウェアを用いるロジスティック回帰モデルを用いてゲノムワイド解析を行った。P値≦10−6を提供したロジスティック回帰検定からの全ての結果をSASソフトウェアv.9.3(SAS Institute Inc.、Cary, NC, USA)で検証し、Cox比例ハザード回帰を用いて検定した。Cox回帰からの結果を、ロジスティック回帰からの結果よりも試験の目的に適していると予め定義し、一次結果として報告することを計画した。また、Cox比例ハザード回帰モデルも使用して、処置群試料及びプラセボ群試料の両方を使用したlog(イベント率)〜遺伝子型+処置群+遺伝子型*処置群+性別+PCにより遺伝子−処置相互作用について検定した。
*遺伝子型により各SNPについて層別化された共変量について調整しない、参照群として共通アレルのホモ接合性遺伝子型とのCox比例ハザード回帰。
*共変量調整を行わずに、遺伝子型群によって層別化された処置効果についてのCox比例ハザード回帰
Claims (36)
- ADCY9遺伝子における1つ以上の多型性部位で応答向上型遺伝子型を有すると同定された対象の、心血管障害を処置するための医薬の製造におけるダルセトラピブの使用であって、1つ以上の多型性部位が:rs1967309、rs12595857、rs2239310、rs11647828、rs8049452、rs12935810、rs74702385、rs17136707、rs8061182、rs111590482、rs4786454、rs2283497、rs2531967、rs3730119、及びrs13337675の1つ以上である、使用。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AA、rs1967309/AG、rs12595857/GG、rs12595857/AG、rs111590482/AG、rs111590482/GG、rs11647828/GG、rs11647828/AG、rs12935810/GG、rs17136707/GG、rs17136707/AG、rs2239310/GG、rs2239310/AG、rs2283497/AA、rs2283497/CA、rs2531967/AA、rs2531967/GA、rs3730119/AA、rs3730119/GA、rs4786454/AA、rs4786454/GA、rs74702385/GA、rs74702385/AA、rs8049452/GG、rs8049452/GA、rs8061182/AA、rs8061182/AG、及びrs13337675/AGの1つ以上である、請求項1記載の使用。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AA、rs12595857/GG、rs111590482/AG、rs111590482/GG、rs11647828/GG、rs12935810/GG、rs17136707/GG、rs2239310/GG、rs2283497/AA、rs2531967/AA、rs3730119/AA、rs4786454/AA、rs74702385/GA、rs74702385/AA、rs8049452/GG及びrs8061182/AAの1つ以上である、請求項1又は2記載の使用。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AAである、請求項1〜3のいずれか一項記載の使用。
- 1つ以上の応答向上型遺伝子型が、rs12595857/GGである、請求項1〜3のいずれか一項記載の使用。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AA及びrs12595857/GGである、請求項1〜3のいずれか一項記載の使用。
- 心血管障害が、心血管疾患、冠動脈心疾患、冠動脈疾患、高脂血症、高リポタンパク血症、アテローム動脈硬化症、末梢血管疾患、脂質異常症、高βリポタンパク血症、低αリポタンパク血症、高コレステロール血症、高トリグリセリド血症、家族性高コレステロール血症、狭心症、虚血、心虚血、卒中、心筋梗塞、再灌流傷害、血管形成術後の再狭窄、高血圧症、又は糖尿病、肥満又は内毒血症の血管合併症である、請求項1〜6のいずれか一項記載の使用。
- 心血管障害が、急性冠症候群である、請求項1〜7のいずれか一項記載の使用。
- ADCY9遺伝子における1つ以上の多型性部位で応答向上型遺伝子型を有すると同定された対象の、心血管イベントのリスクを低下させるための医薬の製造におけるダルセトラピブの使用であって、1つ以上の多型性部位が:rs1967309、rs12595857、rs2239310、rs11647828、rs8049452、rs12935810、rs74702385、rs17136707、rs8061182、rs111590482、rs4786454、rs2283497、rs2531967、rs3730119、及びrs13337675の1つ以上である、使用。
- 応答向上型遺伝子型が、s1967309/AA、rs1967309/AG、rs12595857/GG、rs12595857/AG、rs111590482/AG、rs111590482/GG、rs11647828/GG、rs11647828/AG、rs12935810/GG、rs17136707/GG、rs17136707/AG、rs2239310/GG、rs2239310/AG、rs2283497/AA、rs2283497/CA、rs2531967/AA、rs2531967/GA、rs3730119/AA、rs3730119/GA、rs4786454/AA、rs4786454/GA、rs74702385/GA、rs74702385/AA、rs8049452/GG、rs8049452/GA、rs8061182/AA、rs8061182/AG、及びrs13337675/AGの1つ以上である、請求項9記載の使用。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AA、rs12595857/GG、rs111590482/AG、rs111590482/GG、rs11647828/GG、rs12935810/GG、rs17136707/GG、rs2239310/GG、rs2283497/AA、rs2531967/AA、rs3730119/AA、rs4786454/AA、rs74702385/GA、rs74702385/AA、rs8049452/GG、及びrs8061182/AAの1つ以上である、請求項9記載の使用。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AAである、請求項9記載の使用。
- 1つ以上の応答向上型遺伝子型が、rs12595857/GGである、請求項9記載の使用。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AA及びrs12595857/GGである、請求項9記載の使用。
- 対象が、心血管障害を有する、請求項9〜14のいずれか一項記載の使用。
- 心血管障害が、心血管疾患、冠動脈心疾患、冠動脈疾患、高脂血症、高リポタンパク血症、アテローム動脈硬化症、末梢血管疾患、脂質異常症、高βリポタンパク血症、低αリポタンパク血症、高コレステロール血症、高トリグリセリド血症、家族性高コレステロール血症、狭心症、虚血、心虚血、卒中、心筋梗塞、再灌流傷害、血管形成術後の再狭窄、高血圧症、又は糖尿病、肥満又は内毒血症の血管合併症である、請求項15記載の使用。
- 心血管障害が、急性冠症候群である、請求項15記載の使用。
- 心血管イベントが、心血管死、蘇生された心停止、非致死性心筋梗塞、非致死性虚血性卒中、不安定狭心症、又は予期しない冠血行再建である、請求項9〜17のいずれか一項記載の使用。
- ADCY9遺伝子における1つ以上の多型性部位で応答向上型遺伝子型を有すると同定された対象の、心血管障害を処置するためのダルセトラピブを含む医薬組成物であって、1つ以上の多型性部位が:rs1967309、rs12595857、rs2239310、rs11647828、rs8049452、rs12935810、rs74702385、rs17136707、rs8061182、rs111590482、rs4786454、rs2283497、rs2531967、rs3730119、及びrs13337675の1つ以上である、医薬組成物。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AA、rs1967309/AG、rs12595857/GG、rs12595857/AG、rs111590482/AG、rs111590482/GG、rs11647828/GG、rs11647828/AG、rs12935810/GG、rs17136707/GG、rs17136707/AG、rs2239310/GG、rs2239310/AG、rs2283497/AA、rs2283497/CA、rs2531967/AA、rs2531967/GA、rs3730119/AA、rs3730119/GA、rs4786454/AA、rs4786454/GA、rs74702385/GA、rs74702385/AA、rs8049452/GG、rs8049452/GA、rs8061182/AA、rs8061182/AG、及びrs13337675/AGの1つ以上である、請求項19記載の医薬組成物。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AA、rs12595857/GG、rs111590482/AG、rs111590482/GG、rs11647828/GG、rs12935810/GG、rs17136707/GG、rs2239310/GG、rs2283497/AA、rs2531967/AA、rs3730119/AA、rs4786454/AA、rs74702385/GA、rs74702385/AA、rs8049452/GG、及びrs8061182/AAの1つ以上である、請求項19記載の医薬組成物。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AAである、請求項19記載の医薬組成物。
- 1つ以上の応答向上型遺伝子型が、rs12595857/GGである、請求項19記載の医薬組成物。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AA及びrs12595857/GGである、請求項19記載の医薬組成物。
- 心血管障害が、心血管疾患、冠動脈心疾患、冠動脈疾患、高脂血症、高リポタンパク血症、アテローム動脈硬化症、末梢血管疾患、脂質異常症、高βリポタンパク血症、低αリポタンパク血症、高コレステロール血症、高トリグリセリド血症、家族性高コレステロール血症、狭心症、虚血、心虚血、卒中、心筋梗塞、再灌流傷害、血管形成術後の再狭窄、高血圧症、又は糖尿病、肥満又は内毒血症の血管合併症である、請求項19〜24のいずれか一項記載の医薬組成物。
- 心血管障害が、急性冠症候群である、請求項19〜25のいずれか一項記載の医薬組成物。
- ADCY9遺伝子における1つ以上の多型性部位で応答向上型遺伝子型を有すると同定された対象の、心血管イベントのリスクを低下させるためのダルセトラピブを含む医薬組成物であって、1つ以上の多型性部位が:rs1967309、rs12595857、rs2239310、rs11647828、rs8049452、rs12935810、rs74702385、rs17136707、rs8061182、rs111590482、rs4786454、rs2283497、rs2531967、rs3730119、及びrs13337675の1つ以上である、医薬組成物。
- 応答向上型遺伝子型が、rs1967309/AA、rs1967309/AG、rs12595857/GG、rs12595857/AG、rs111590482/AG、rs111590482/GG、rs11647828/GG、rs11647828/AG、rs12935810/GG、rs17136707/GG、rs17136707/AG、rs2239310/GG、rs2239310/AG、rs2283497/AA、rs2283497/CA、rs2531967/AA、rs2531967/GA、rs3730119/AA、rs3730119/GA、rs4786454/AA、rs4786454/GA、rs74702385/GA、rs74702385/AA、rs8049452/GG、rs8049452/GA、rs8061182/AA、rs8061182/AG、及びrs13337675/AGの1つ以上である、請求項27記載の医薬組成物。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AA、rs12595857/GG、rs111590482/AG、rs111590482/GG、rs11647828/GG、rs12935810/GG、rs17136707/GG、rs2239310/GG、rs2283497/AA、rs2531967/AA、rs3730119/AA、rs4786454/AA、rs74702385/GA、rs74702385/AA、rs8049452/GG、及びrs8061182/AAの1つ以上である、請求項27記載の医薬組成物。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AAである、請求項27記載の医薬組成物。
- 1つ以上の応答向上型遺伝子型が、rs12595857/GGである、請求項27記載の医薬組成物。
- 1つ以上の応答向上型遺伝子型が、rs1967309/AA及びrs12595857/GGである、請求項27記載の医薬組成物。
- 対象が、心血管障害を有する、請求項27〜32のいずれか一項記載の医薬組成物。
- 心血管障害が、心血管疾患、冠動脈心疾患、冠動脈疾患、高脂血症、高リポタンパク血症、アテローム動脈硬化症、末梢血管疾患、脂質異常症、高βリポタンパク血症、低αリポタンパク血症、高コレステロール血症、高トリグリセリド血症、家族性高コレステロール血症、狭心症、虚血、心虚血、卒中、心筋梗塞、再灌流傷害、血管形成術後の再狭窄、高血圧症、又は糖尿病、肥満又は内毒血症の血管合併症である、請求項33記載の医薬組成物。
- 心血管障害が、急性冠症候群である、請求項33記載の医薬組成物。
- 心血管イベントが、心血管死、蘇生された心停止、非致死性心筋梗塞、非致死性虚血性卒中、不安定狭心症、又は予期しない冠血行再建である、請求項27〜35のいずれか一項記載の医薬組成物。
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