JP6395061B2 - How to assess the risk of side effects of drugs induced by phenytoin - Google Patents
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Description
本発明は患者の薬の副作用に対するリスクを予測する方法に関し、特に、フェニトインに対する薬の副作用を発症するリスク評価に関する。 The present invention relates to a method for predicting the risk of side effects of a drug on a patient, and more particularly to risk assessment for developing the side effect of the drug on phenytoin.
薬の副作用(略称はADRs)とは通常の投与量で与えられた薬物の使用に伴う害のことである。薬剤過敏症は医療における一般的な有害事象であり、20%は薬の副作用として報告されている。これら過敏反応は過敏性皮膚発疹(MPE)から致死的な薬物反応である好酸球増加および全身症状症候群(DRESS)、スティーブンス・ジョンソン症候群(SJS)又は中毒性表皮剥離症(TEN)として現れる。 Drug side effects (abbreviated as ADRs) are harms associated with the use of drugs given at normal doses. Drug hypersensitivity is a common adverse event in medicine, with 20% reported as a drug side effect. These hypersensitivity reactions appear from hypersensitivity skin rash (MPE) to fatal drug reaction, eosinophilia and systemic symptom syndrome (DRESS), Stevens-Johnson syndrome (SJS) or toxic epidermis detachment (TEN) .
フェニトイン、カルバマゼピン又はラモトリジンなどの多くの芳香性抗てんかん薬(AEDs)はよく過敏性反応と関連付けられる。特に、フェニトインは第一線のAEDであるが、フェニトインを受け取った19%の患者は過敏性反応を発症する。過去の研究によって、ミクロソームエポキシド水酸化酵素及びヒト白血球抗原(HLA)のサブタイプの欠如がAED過敏性と関連付けられると示された。しかし、薬物代謝/遺伝的感受性とフェニトインによって誘発される過敏性反応の間の関係はやはり不明確である。 Many aromatic antiepileptic drugs (AEDs) such as phenytoin, carbamazepine or lamotrigine are often associated with hypersensitivity reactions. In particular, phenytoin is a first-line AED, but 19% of patients who receive phenytoin develop a hypersensitivity reaction. Previous studies have shown that the lack of microsomal epoxide hydroxylase and human leukocyte antigen (HLA) subtypes are associated with AED hypersensitivity. However, the relationship between drug metabolism / genetic susceptibility and hypersensitivity reactions induced by phenytoin is still unclear.
したがって、CYP2C9の遺伝子学的多様性、フェニトイン血漿濃度及びHLA遺伝子型を含む要素を評価することによってリスクを評価することができる、フェニトインによって誘発される過敏性のリスクを予測する新しくて改良された方法が必要とされている。 Thus, a new and improved prediction of the risk of phenytoin-induced hypersensitivity can be assessed by assessing factors including genetic diversity of CYP2C9, phenytoin plasma concentration and HLA genotype A method is needed.
本発明は特に重大な皮膚の有害反応であるSJS、TEN及びDRESSといったフェニトインによって誘発される薬の副作用を患者が発症するリスクを評価する方法を提供する。SJS、TEN、DRESSを含む、58のフェニトインによって誘発される深刻な皮膚の薬の副作用(SCARs)及び198の制御の全ゲノム関連解析(アフィメトリクス6.0)を用いる。ある実施形態では、患者がフェニトインによって誘発される薬の副作用を発症するリスクを評価する方法は、フェニトインによって誘発さえる過敏性と関連付けられるCYP2Cs領域の第10染色体上の単一ヌクレオチド多型(SNPs)、例えば、CYP2C18上のrs17110192、rs7896133;CYP2C9上のrs1057910(CYP2C9*3)、rs17110321、rs9332093、rs9332245;CYP2C19上のrs3758581、rs2860905、rs4086116及びCYP2C8上のrs7899038、rs1592037、rs1934952、rs11572139、rs6583967の存在を検出するステップを含む。 The present invention provides a method for assessing a patient's risk of developing side effects of phenytoin-induced drugs such as SJS, TEN and DRES, which are particularly serious skin adverse reactions. We use 58 phenytoin-induced serious skin drug side effects (SCARs) and 198 control genome-wide association analysis (Affymetrix 6.0), including SJS, TEN, and DRESS. In certain embodiments, a method for assessing a patient's risk of developing phenytoin-induced drug side effects is a single nucleotide polymorphism (SNPs) on chromosome 10 of the CYP2Cs region associated with hypersensitivity induced by phenytoin. Rs17110192, rs798963 on CYP2C18; rs1057910 on CYP2C9 (CYP2C9 * 3); Detecting.
別の実施形態では、患者がフェニトインによって誘発される薬の副作用を発症するリスクを評価する方法は、フェニトイン耐性対照群と比べて、フェニトインによって誘発されるSJS/TEN/DRESSと関連付けられる統計的重要性を増加させることができるハプロタイプに属するrs1057910(CYP2C9*3)、rs3758581、rs17110192、rs9332245又はrs1592037(特にrs17110192、rs1057910及びrs3758581)を結合させるステップを含む。rs1057910、rs3758581、rs17110192、rs9332245、rs1592037(特にrs1057910及びrs3758581、0/95)の結合を保有する耐フェニトイン個人はいないが、約三分の一のフェニトイン敏感性患者はこの結合を保有している(30/96)。これらSNPsのいくつかはアミノ酸配列の変化を引き起こす。例えば、rs3758581について、CYP2C19エクソン7のミスセンス変化はフェニトイン−SJS/TEN/DRESSと強く関連付けられる。CYP2C9*3はフェニトインによって誘発されるSJS/TEN/DRESSと強い関連を有する。 In another embodiment, the method of assessing a patient's risk of developing phenytoin-induced drug side effects is associated with statistical significance associated with phenytoin-induced SJS / TEN / DRES as compared to a phenytoin-resistant control group Binding rs1057910 (CYP2C9 * 3), rs3758581, rs17110192, rs93332245 or rs15992037 (especially rs17110192, rs1057910 and rs3758581) belonging to a haplotype capable of increasing sex. Although no phenytoin-resistant individuals possess the binding of rs1057910, rs3758581, rs17110192, rs93332245, rs1592037 (especially rs1057910 and rs3758581, 0/95), about one third of phenytoin-sensitive patients have this binding ( 30/96). Some of these SNPs cause amino acid sequence changes. For example, for rs3758581, the missense change in CYP2C19 exon 7 is strongly associated with phenytoin-SJS / TEN / DRES. CYP2C9 * 3 has a strong association with SJS / TEN / DRES induced by phenytoin.
別の実施形態では、本発明は患者がフェニトインによって誘発される薬の副作用を発症するリスクを評価する方法を提供し、候補遺伝子(CYP2Cs及びHLA)を使用して、フェニトインによって誘発される過敏性反応を有する152の患者にアプローチし、53ケースのフェニトイン−SJS/TEN、24ケースのフェニトイン−DRESS及び75ケースのフェニトイン−MPE及びいかなる有害反応なしに3ヶ月以上フェニトインを受け取った118の耐性対照群を含む。結果、30.2%のフェニトイン−SJS/TEN及び37.5%のフェニトイン−DRESSはCYP2C9*3を保有していた。一方、14.7%のフェニトイン−MPE及び2.5%の耐性対照群のみがCYP2C9*3遺伝子型を保有していた。本発明はCYP2C9の遺伝異形及び、CYP2C19、CYP2C8及びCYP2C18は乏しいフェニトインの代謝活動と関連しており、過敏性反応につながる血漿内の薬物貯蓄の増加を指し示している。CYP2Csの遺伝的つながりに加え、HLA−A*0207、HLA−A*2402、HLA−B*1301、HLA−B*1502、HLA−B*4001、HLA−B*4609、HLA−B*5101、HLA−DRB1*1001又はHLA−DRB1*1502もフェニトインによって誘発される過敏性との有意な関連を示した。よって、これらデータからCYP2C9/2C19/2C8/2C18の遺伝子学的多様性又はその欠陥対立遺伝子、フェニトイン血漿レベル及び特定のHLA遺伝子型のすべてがフェニトインによって誘発される重大な皮膚の薬の副作用に寄与することが示されている。 In another embodiment, the present invention provides a method for assessing a patient's risk of developing phenytoin-induced drug side effects, and using candidate genes (CYP2Cs and HLA), hypersensitivity induced by phenytoin. 152 resistant controls who approached 152 patients with response and received 53 cases of phenytoin-SJS / TEN, 24 cases of phenytoin-DRES and 75 cases of phenytoin-MPE and no adverse reactions for more than 3 months including. Results 30.2% phenytoin-SJS / TEN and 37.5% phenytoin-DRES possessed CYP2C9 * 3. On the other hand, only 14.7% phenytoin-MPE and 2.5% resistance control group possessed CYP2C9 * 3 genotype. The present invention refers to genetic variants of CYP2C9, and CYP2C19, CYP2C8 and CYP2C18 are associated with poor metabolic activity of phenytoin, indicating increased drug storage in plasma leading to hypersensitivity reactions. In addition to the genetic linkage of CYP2Cs, HLA-A * 0207, HLA-A * 2402, HLA-B * 1301, HLA-B * 1502, HLA-B * 4001, HLA-B * 4609, HLA-B * 5101, HLA-DRB1 * 1001 or HLA-DRB1 * 1502 also showed a significant association with hypersensitivity induced by phenytoin. Thus, from these data, the genetic diversity of CYP2C9 / 2C19 / 2C8 / 2C18 or its defective alleles, phenytoin plasma levels and certain HLA genotypes all contribute to the significant skin drug side effects induced by phenytoin Has been shown to do.
以下の詳細な説明は本発明の観点に基づく実施形態の説明を意図しており、本発明が応用される唯一の形態を示すことを意図しているわけではなく、むしろ、これは本発明の精神や範囲に基づき、同一又は同等の機能や構成を達成する異なった実施形態をも含むことを意図している。 The following detailed description is intended as a description of embodiments in accordance with aspects of the invention and is not intended to represent the only form in which the invention is applied, but rather is It is intended to include different embodiments that achieve the same or equivalent functions and configurations based on spirit and scope.
定義されないのであれば、ここでのすべての技術及び科学用語は当業者が一般的に理解する意味と同じである。本発明を実施する、又はテストするために、記載されている方法、装置及び物質と同等のいかなるものであっても使用することができるが、以下では、ある実施形態における方法、装置及び物質を記載する。 Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any equivalents of the described methods, apparatus and materials may be used to practice or test the present invention, the methods, apparatus and materials in certain embodiments are described below. Describe.
すべての言及されている公開物は詳細な説明及び開示の目的のため、引用文献として含まれ、例えば、公開物に記載されている設計及び方法論は本発明と関連して用いることができる。上記、下記、また文章中で記載されている公開物は本願の出願日前の文献を開示する目的のためだけに提供される。また、ここには、先行発明として開示されているため、発明者が権利を有していないものとして解釈されるものはない。 All mentioned publications are incorporated by reference for purposes of detailed description and disclosure, for example, the designs and methodologies described in the publications can be used in connection with the present invention. The publications described above, below, and in the text are provided solely for the purpose of disclosing documents prior to the filing date of the present application. Moreover, since it is disclosed here as a prior invention, there is nothing that the inventor does not interpret as having no rights.
スティーブンス・ジョンソン症候群(SJS)及び中毒性表皮剥離症(TEN)の診断は合意基準(Bastuji-Garin S, Rzany B et al, 1993)によって定義される臨床上の形態学に基づくものである。SJSは<体の表面領域の10%、SJS_TEN重複が皮膚剥離の10−29%及びTEN>/=30%と定義される。DRESSの基準は好酸球増多症、非定型循環リンパ球、急性肝細胞損傷、又は腎機能の悪化といった症状を伴う皮膚疹(例えば、拡散丘疹、剥脱性皮膚炎)である((Kardaun SH, Sidoroff A et al, 2007)。フェニトインによって誘発されたSJS、TEN、DRESSの診断基準を満たす患者は長庚紀念病院で特定され、この研究に登録された。 The diagnosis of Stevens-Johnson syndrome (SJS) and toxic epidermolysis (TEN) is based on clinical morphology defined by consensus criteria (Bastuji-Garin S, Rzany B et al, 1993). SJS is defined as <10% of body surface area, SJS_TEN overlap is 10-29% of dermabrasion and TEN> / = 30%. The criteria for DRESS is skin rash (eg, diffuse papules, exfoliative dermatitis) with symptoms such as eosinophilia, atypical circulating lymphocytes, acute hepatocyte damage, or impaired renal function ((Kardaun SH , Sidoroff A et al, 2007) Patients who met the diagnostic criteria of SJS, TEN, and DRES induced by phenytoin were identified at the Nagatoro Memorial Hospital and enrolled in this study.
CYP2C9、CYP2C19、CYP2C8及びCYP2C18を含む特定のCYP2C遺伝子異形はフェニトインの低代謝活動と関連することが発見され、フェニトインによって誘発される過敏性反応と関連付けられることが発見された。CYP2C異形に加え、HLA−A*0207、HLA−A*2402、HLA−B*1301、HLA−B*1502、HLA−B*4001、HLA−B*4609、HLA−B*5101、HLA−DRB1*1001又はHLA−DRB1*1502もフェニトインによって誘発される過敏性又は皮膚の薬の副作用との強い関連を示すことが発見された。 It has been discovered that certain CYP2C gene variants, including CYP2C9, CYP2C19, CYP2C8 and CYP2C18, are associated with phenytoin hypometabolic activity and associated with hypersensitivity reactions induced by phenytoin. In addition to CYP2C variants, HLA-A * 0207, HLA-A * 2402, HLA-B * 1301, HLA-B * 1502, HLA-B * 4001, HLA-B * 4609, HLA-B * 5101, HLA-DRB1 * 1001 or HLA-DRB1 * 1502 was also found to show a strong association with phenytoin-induced hypersensitivity or side effects of skin drugs.
したがって、本発明はフェニトインによって誘発される薬の副作用のリスクを評価する方法を提供し、CYP2C9、CYP2C19、CYP2C8及びCYP2C18を含むCYP2C領域の第10染色体上の単一ヌクレオチド多型(SNPs)の存在を検出するステップを含む。58のフェニトインによって誘発されるSCARs(SJS、TEN及びDRESSを含む)及び198の個体数の対照群の全ゲノム関連解析(アフィメトリクス6.0)を用いることによって、最も重要なSNPsはCYP2C領域の第10染色体(図1参照)、例えば、CYP2C18のrs17110192、rs7896133;CYP2C9のrs17110321、rs9332093、rs9332245;CYP2C19のrs3758581、rs2860905、rs4086116及びCYP2C8のrs7899038、rs1592037、rs1934952、rs11572139、rs6583967にあることがわかった(表1参照)。CYP2C遺伝子座の近くに位置する他のSNPs、例えば、rs2274222、rs11188183、rs7921561、rs10882544、rs7084271、rs644437、rs12769577、rs617848、rs10882551、rs585381、rs648638、rs664093、rs12262878、rs17524438、rs12413028、rs11188246、rs12415795、rs11596107、rs11596737、rs10509685、rs7912686、rs17453729、rs17453764、rs17526000及びrs12769370もフェニトインによって誘発される過敏性反応と強い関連がある(表1参照)。 Accordingly, the present invention provides a method for assessing the risk of side effects of drugs induced by phenytoin and the presence of single nucleotide polymorphisms (SNPs) on chromosome 10 of the CYP2C region, including CYP2C9, CYP2C19, CYP2C8 and CYP2C18 Detecting. By using a genome-wide association analysis (Affymetrix 6.0) of 58 phenytoin-induced SCARs (including SJS, TEN and DRES) and a control group of 198 individuals, the most important SNPs are the number of CYP2C regions. 10 chromosomes (see FIG. 1), for example, rs17110192, rs78996133 of CYP2C18; rs17110321 of CYP2C9; (See Table 1). Other SNPs located near the CYP2C locus, e.g., rs2274222, rs11188183, rs7921561, rs10882544, rs7084271, rs6445437, rs1276954s, rs126874s, rs6124srs rs11596737, rs10509655, rs7912686, rs174453729, rs17445364, rs17526000 and rs12769370 are also strongly associated with the hypersensitivity response induced by phenytoin (see Table 1).
過去の研究ではCYP2C9*3はフェニトインによって誘発される斑丘疹性発疹(MPE)のリスクを増加させることが指摘されている(Lee AY. et al. 2004)。ある実施形態では、CYP2C9*3はフェニトインによって誘発される薬の副作用のリスクを予測するために用いられる。他のタイプのフェニトインによって誘発される薬の副作用(ADRs)、特にSJS又はTENの特異な皮膚と粘膜の水疱形成の表現型に対するCYP2C9*3の役割を調べるため、単一ヌクレオチド多型(SNP)遺伝子型決定がフェニトインによって誘発された薬の副作用を有する患者に対して行われた。152の患者がこのフェニトインによって誘発される過敏性反応の研究に登録され、53ケースのフェニトイン−SJS/TEN、24ケースのフェニトイン−DRESS及び75ケースのフェニトイン−MPE及びいかなる有害反応なしに3ヶ月以上フェニトインを受け取った118の耐性対照群を含む。結果、CYP2C9*3異形は53中16(30.2%)のフェニトインによって誘発されたSJS/TEN患者、24中9(37.5%)のフェニトインによって誘発されたDRESS患者、75中11(14.7%)のフェニトインによって誘発されたMPEで存在が見られた。一方、異形は2.5%(3/118)のフェニトイン耐性グループで見られただけであった(表2参照)。フェニトイン過敏性ケース及び耐性対照群の統計的分析により、CYP2C9*3異形はフェニトインによって誘発されるSJS/TEN(SJS/TEN vs. 耐性対照群:P=3.3´10-7, OR=17.5
(4.8-63.7)又はDRESS(DRESS vs. 耐性対照群:P =6.1´10-5, OR=19.2 (4.4-82.7))と最も強く関連付けられることが示されたが、フェニトイン−MPEとの関連は弱く(MPE vs. 耐性対照群:P=0.004, OR=6.2 (1.6-23.3))、このCYP2C9*3異形の存在はフェニトインによって誘発されるADRs、特にフェニトインによって誘発されるSJS/TEN又はDRESSの高いリスクの患者を特定するために用いることができる。
Previous studies have indicated that CYP2C9 * 3 increases the risk of phenytoin-induced maculopapular rash (MPE) (Lee AY. Et al. 2004). In one embodiment, CYP2C9 * 3 is used to predict the risk of drug side effects induced by phenytoin. To investigate the role of CYP2C9 * 3 on drug-induced side effects (ADRs) induced by other types of phenytoin, particularly the unique skin and mucosal blistering phenotype of SJS or TEN, single nucleotide polymorphisms (SNPs) Genotyping was performed on patients with drug side effects induced by phenytoin. 152 patients were enrolled in this study of hypersensitivity reactions induced by phenytoin, 53 cases of phenytoin-SJS / TEN, 24 cases of phenytoin-DRESS and 75 cases of phenytoin-MPE and for more than 3 months without any adverse reaction Includes 118 resistant control groups that received phenytoin. Results CYP2C9 * 3 variants were SJS / TEN patients induced by 16 (30.2%) phenytoin in 53, DRESS patients induced by 9 (37.5%) phenytoin in 24, 11 out of 75 (14 Presence was found in MPE induced by .7%) phenytoin. On the other hand, variants were only seen in the 2.5% (3/118) phenytoin resistant group (see Table 2). Statistical analysis of the phenytoin hypersensitivity case and the resistance control group shows that the CYP2C9 * 3 variant is phenytoin-induced SJS / TEN (SJS / TEN vs. resistance control group: P = 3.3'10-7, OR = 17.5
(4.8-63.7) or DRES (DRESs vs. resistance control group: P = 6.1'10-5, OR = 19.2 (4.4-82.7)), but the association with phenytoin-MPE Is weak (MPE vs. resistance control group: P = 0.004, OR = 6.2 (1.6-23.3)), and the presence of this CYP2C9 * 3 variant is ADRs induced by phenytoin, particularly SJS / TEN or DRES induced by phenytoin Can be used to identify high-risk patients.
別の実施形態では、アミノ核酸の変化を引き起こすCYP2CのSNPsをフェニトインによって誘発される薬の副作用のリスクを評価するために用いることができる。いくつかのアミノ核酸を変化させることができるCYP2C遺伝子のSNPs、例えば、CYP2C9の371G > A(rs12414460、Arg124Gln)、895A > G、(rs72558192、Thr299Ala、CYP2C9*16として知られる)、1362G > C(Gln454His、CYP2C9*19として知られる);CYP2C19の991A> G(rs3758581, Ile331Val)、395G > A(rs72558184、Arg132Gln、CYP2C19*6として知られる)、636G > A(rs4986893、Trp212end、CYP2C19*3として知られる)、681G > A、(rs4244285、スプライシング・サイト・変形を引き起こす、CYP2C19*2として知られる)、781C > T(Arg261Trp)及びCYP2C18の204T > A(rs41291550、Tyr68end)、370C > T(Arg124Trp)、576G > C(Gln192His)、1154C > T(rs2281891、Thr385Met)に対するさらなる研究がなされた。CYP2C酵素のこれら変化はその活動及びその基質の特異性の両方に影響を与えうる。例えば、rs3758581、CYP2C19エクソン7のミスセンス変化はフェニトイン−SJS/TEN/DRESS(SJS/TEN/DRESS vs. 耐性:P=0.0003, OR=7.28 (2.3564-22.4912))と強く関連付けられる(表1参照)。
また、本発明の別の実施形態では、異なるSNPsを組み合わせてフェニトインによって誘発される薬の副作用のリスクを評価した。ハプロタイプに属するrs1057910
(CYP2C9*3)、rs3758581、rs17110192、rs9332245 又はrs1592037は、フェニトイン耐性対照群と比べて、フェニトインによって誘発されるSJS/TEN/DRESSと関連する統計的重要性を増加させることができることがわかった。特に患者がrs1057910とrs3758581又はrs17110192の両方を保有しているとき、フェニトインによって誘発されるSJS/TEN/DRESSとより有意な関連を持つ(表3参照)。
In another embodiment of the present invention, different SNPs were combined to assess the risk of side effects of drugs induced by phenytoin. Rs1057910 belonging to haplotype
(CYP2C9 * 3), rs3758581, rs17110192, rs93332245 or rs1592037 were found to be able to increase the statistical significance associated with phenytoin-induced SJS / TEN / DRESS compared to the phenytoin resistant control group. There is a more significant association with phenytoin-induced SJS / TEN / DRES, especially when patients have both rs1057910 and rs3758581 or rs17110192 (see Table 3).
さらなる実施形態では、本発明はフェニトインによって誘発される薬の副作用のリスクを評価する方法が提供され、HLA−A、HLA−B、HLA−DRB1を含むHLA遺伝子型の存在を特定するステップを含む。フェニトイン−ADRs患者のHLA−A、HLA−B及びHLA−DRB1遺伝子型、及び耐性対照群を特定するため、PCR−SSOが用いられる。結果、HLA−A*0207、HLA−A*2402、HLA−B*1301、HLA−B*1502、HLA−B*4001、HLA−B*4609、HLA−B*5101、HLA−DRB1*1001又はHLA−DRB1*1502はフェニトインによって誘発されるADRs(SJS/TEN/DRESS又はMPE)と有意に関連付けられることが示された(表4−6参照)。また、データから耐性対照群と比べて、フェニトイン−ADRsを有する患者の間でHLA−B*1301対立遺伝子は大幅に頻度が増加した。15のSJS/TEN患者(28.3%)及び12のDRESS患者(46.2%)はHLA−B*1301を保有し、14の耐性患者(11.9%)だけがこの遺伝子型を保有していた(SJS/TEN vs. 耐性対照群: P=0.001, OR=3.8 (1.7-8.5); DRESS vs. 耐性対照群: P =2´10-4, OR=6.4 (2.5-16.5))。しかし、この関連はMPEにおいては有意ではない(MPE vs. 耐性対照群: P=0.296, OR=1.7 (0.7-3.7))。HLA−B*5101対立遺伝子もフェニトインによって誘発されるADRsと関連付けられる。13.2%のSJS/TEN患者、19.2%のDRESS患者及び15.6%のMPE患者はHLA−B*5101を保有し、一方、5の耐性患者(4.2%)だけがこの遺伝子型を保有していた(SJS/TEN vs. 耐性対照群: P=0.05, OR=3.4; DRESS vs. 耐性対照群: P=0.018, OR=5.4; MPE vs. 耐性対照群: P=0.009, OR=4.2)。
我々の過去の研究によれば、HLA−B*1502対立遺伝子はカルバマゼピンによって誘発されるSJS/TENと強く関連付けられることが示されている(Chung WH et al, 2004)。本願のさらなる実施形態では、HLA−B*1502対立遺伝子はフェニトインによって誘発される薬の副作用のリスクを評価するために用いられ、HLA−B*1502はフェニトインによって誘発されるADRsと関連付けられることが示されている。12のSJS/TEN患者(22.6%)がHLA−B*1502を保有しており、一方、9の耐性患者(7.6%)だけがこの遺伝子型を保有していた。耐性対照群と比べて、フェニトインによって誘発されるSJS/TEN患者の間でHLA−B*1502対立遺伝子は大幅に頻度が増加した(SJS/TEN vs. 耐性: P=0.01, OR=3.5 (1.4-9.0))。しかしながら、フェニトインによって誘発されるDRESS及びMPEでは関連は見られなかった(P>0.05)。 Our previous studies have shown that the HLA-B * 1502 allele is strongly associated with SJS / TEN induced by carbamazepine (Chung WH et al, 2004). In a further embodiment of the present application, the HLA-B * 1502 allele may be used to assess the risk of phenytoin-induced drug side effects, and HLA-B * 1502 may be associated with phenytoin-induced ADRs. It is shown. Twelve SJS / TEN patients (22.6%) had HLA-B * 1502, whereas only 9 resistant patients (7.6%) had this genotype. Compared to the resistance control group, the HLA-B * 1502 allele was significantly more frequent among SJS / TEN patients induced by phenytoin (SJS / TEN vs. resistance: P = 0.01, OR = 3.5 (1.4 -9.0)). However, no association was found with DDR and MPE induced by phenytoin (P> 0.05).
さらに本発明では、耐性対照群と比べて、フェニトインによって誘発されるDRESS患者の間でHLA−B*4609対立遺伝子は大幅に頻度が増加し(DRESS vs. 耐性対照群: P=0.032, OR=19.7 (0.9-449.8))、HLA−A*0207対立遺伝子はフェニトインによって誘発されるDRESSと関連付けられることがわかった(DRESS vs. 耐性対照群: P=0.024, OR=4.6 (1.3-16.2))。さらに、HLA−DRB1*1001はフェニトインによって誘発されるMPEと関連付けられることがわかった(MPE vs. 耐性対照群: P=0.02, OR=13.2);HLA−DRB1*1502はフェニトインによって誘発されるSJS/TEN(SJS/TEN vs. 耐性対照群: P=0.029, OR=14)と関連付けられることがわかった。一方、HLA−A*2402及びHLA−B*4001対立遺伝子はフェニトインによって引き起こされるADRsの保護効果(フェニトインによって誘発されるADRsでは対立遺伝子頻度を下げ、耐性対照群では増加させる)を示した。
研究によれば、CYP2C19、CYP2C8、CYP2C18及び、CYP2C9の遺伝子異形は乏しいフェニトインの代謝活動と関連しており、フェニトイン過敏性反応のリスクにつながるその薬物貯蓄を増加していた。ある実施形態では、フェニトインによって誘発される薬の副作用のリスクを評価する方法は血漿中のフェニトイン濃度を検知するステップを含む。フェニトインは肝酵素によって代謝されるため、シトクロムP450酵素の多型性はフェニトイン血漿濃度に影響を与える。フェニトインの非線形薬物動態及び狭い治療濃度域は血漿のフェニトイン濃度はその有効性と毒性と関連していることを指し示している。 Studies have shown that CYP2C19, CYP2C8, CYP2C18, and CYP2C9 gene variants are associated with poor metabolic activity of phenytoin, increasing its drug storage leading to the risk of phenytoin hypersensitivity reactions. In certain embodiments, a method for assessing the risk of side effects of a drug induced by phenytoin comprises detecting phenytoin concentration in plasma. Since phenytoin is metabolized by liver enzymes, the polymorphism of the cytochrome P450 enzyme affects phenytoin plasma concentrations. Non-linear pharmacokinetics and a narrow therapeutic window of phenytoin indicate that plasma phenytoin concentration is associated with its efficacy and toxicity.
この研究では、ADRの発症の間のフェニトイン濃度はHPLC分析による患者の血漿から決定され、非線形の薬物動態式によって予測される:
Km = 4mg/L (代謝率はVmaxの半分である基質濃度)
Vmax = 7mg/kg/day (最大代謝率)
Vd = 0.65L/kg (分配の量)
t:2つのフェニトイン血漿濃度間の時間(日にち)
In this study, phenytoin concentrations during the onset of ADR are determined from patient plasma by HPLC analysis and predicted by a non-linear pharmacokinetic equation:
Km = 4mg / L (Substrate concentration where metabolic rate is half of Vmax)
Vmax = 7mg / kg / day (maximum metabolic rate)
Vd = 0.65L / kg (amount of distribution)
t: Time between two phenytoin plasma concentrations (date)
フェニトインの治療レベルは通常10−20μg/mlの間である。薬物を摂取後、耐性対照群患者のフェニトイン血漿レベルは5−15μg/mlの間であった。しかし、SJS/TEN患者において、フェニトイン血漿レベルは40−50μg/mlであり、これは耐性対照群患者のものより高くなっていた(SJS/TEN vs. 耐性対照群: P=0.006; MPE vs. 耐性対照群: P=0.004)(図2参照)。また、我々はCYP2Cs異形を保有している患者のフェニトイン血漿レベルを比較した。結果を見ると、CYP2C9*3を保有するフェニトイン−ADRs患者はフェニトイン血漿レベルが高いことが示されている。23のフェニトイン−ADRs患者のフェニトインレベルを分析した後、4人の患者のフェニトインレベルは10μg/mlより低く、9人の患者のフェニトインレベルは10−20μg/mlであり、10人の患者のフェニトインレベルは20μg/mlより高かった。これら23人の患者の中で、CYP2C9*3異形を保有する5人の患者のフェニトイン濃度はどれも20μg/mlより高かった。本発明はCYP2Cs異形、特にCYP2C9*3は、乏しいフェニトインの代謝活動を示し、過敏性反応を引き起こすことを証明している。フェニトインの代謝障害は薬物貯蓄のリスクを増加させる可能性があり、重大な過敏性反応、SJS、TEN、DRESS、を誘発するリスクを引き起こす。 The therapeutic level of phenytoin is usually between 10-20 μg / ml. After taking the drug, the phenytoin plasma levels of the resistant control group patients were between 5-15 μg / ml. However, in SJS / TEN patients, phenytoin plasma levels were 40-50 μg / ml, which was higher than that of patients in the resistant control group (SJS / TEN vs. resistant control group: P = 0.006; MPE vs. Resistant control group: P = 0.004) (see FIG. 2). We also compared phenytoin plasma levels in patients carrying CYP2Cs variants. The results show that phenytoin-ADRs patients carrying CYP2C9 * 3 have high phenytoin plasma levels. After analyzing the phenytoin levels of 23 phenytoin-ADRs patients, the phenytoin level of 4 patients is lower than 10 μg / ml, the phenytoin level of 9 patients is 10-20 μg / ml, and the phenytoin levels of 10 patients The level was higher than 20 μg / ml. Among these 23 patients, 5 patients carrying the CYP2C9 * 3 variant all had phenytoin concentrations higher than 20 μg / ml. The present invention demonstrates that CYP2Cs variants, in particular CYP2C9 * 3, exhibit poor phenytoin metabolic activity and cause hypersensitivity reactions. Impaired metabolism of phenytoin can increase the risk of drug storage, causing the risk of inducing serious hypersensitivity reactions, SJS, TEN, and DRES.
CYP2Cs異形及びHLA遺伝子型はその領域で知られている方法を用いることによって検知することができる。好ましくは関心のある異形に対して特定である調査のため、ゲノムのDNAがハイブリダイズとして生じさせられる。調査は直接の発見としてラベル付けされる、又は調査において特定される第二の、検出可能な分子によって接触される。または、異形のcDNA、RNA又はプロテイン生成物を見つけることができる。 CYP2Cs variants and HLA genotypes can be detected by using methods known in the region. Preferably, genomic DNA is generated as a hybrid for investigations that are specific for the variant of interest. The survey is labeled as a direct finding or contacted by a second, detectable molecule identified in the survey. Alternatively, variant cDNA, RNA or protein products can be found.
以上、本発明を記述及び図示によって説明したが、これらは発明の実施形態であるだけであり、限定として考慮されるものではない。よって、具体的な構成はこの実施形態に限られるものではなく、本発明の要旨を逸脱しないいかなる同等物も含まれる。
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Lee, A.Y., Kim, M.J., Chey, W.Y., Choi, J. & Kim, B.G. Genetic polymorphism of cytochrome P450 2C9 in diphenylhydantoin-induced cutaneous adverse drug reactions. Eur J Clin Pharmacol 60, 155-159 (2004).
Hung, S.I., et al. Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics 11, 349-356 (2010).
Bastuji-Garin S, Rzany B, Stern RS, et al, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129, 92-6 (1993).
Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici BB, Mockenhaupt M, et al. Variabilityin the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 156, 609-11 (2007).
Although the present invention has been described above by description and illustration, these are only embodiments of the invention and are not to be considered as limiting. Therefore, the specific configuration is not limited to this embodiment, and any equivalent that does not depart from the gist of the present invention is included.
[reference]
Ingelman-Sundberg, M. Pharmacogenomic biomarkers for prediction of severe adverse drug reactions.N Engl J Med 358, 637-639 (2008).
Bohan, KH, et al. Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical
care. Pharmacotherapy. 27 (10), 1425-1439 (2007).
Odani, A., et al. Genetic polymorphism of the CYP2C subfamily and its effect on the harmacokinetics of phenytoin in Japanese patients with epilepsy.Clin Pharmacol Ther
62, 287-292 (1997).
Shintani, et al. Genetic polymorphisms and functional characterization of the 5´-flanking region of the human CYP2C9 gene: In vitro and in vivo studies. Clin Pharmacol Ther. 70 (2), 175-182 (2001).
Lee, AY, Kim, MJ, Chey, WY, Choi, J. & Kim, BG Genetic polymorphism of cytochrome P450 2C9 in diphenylhydantoin-induced cutaneous adverse drug reactions.Eur J Clin Pharmacol 60, 155-159 (2004).
Hung, SI, et al. Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese.Pharmacogenomics 11, 349-356 (2010).
Bastuji-Garin S, Rzany B, Stern RS, et al, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129, 92-6 (1993 ).
Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici BB, Mockenhaupt M, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 156, 609-11 (2007).
Claims (4)
前記HLA対立遺伝子の存在をスティーブンス・ジョンソン症候群(SJS)、中毒性表皮剥離症(TEN)、好酸球増加および全身症状症候群(DRESS)、又は斑丘疹性発疹(MPE)を含むフェニトインによって誘発される薬の副作用のリスクを増加させるものとして関連付けるステップと、
を含むことを特徴とする、患者がフェニトインによって誘発される薬の副作用(ADRs)を発症するリスクを評価する方法。 At least one selected from HLA-A * 0207 , HLA-B * 1301, HLA-B * 5101, HLA-B * 4609, HLA-B * 4001, HLA-DRB1 * 1001, and HLA-DRB1 * 1502 Detecting the presence of an HLA allele;
Presence of the HLA allele is induced by phenytoin including Stevens-Johnson syndrome (SJS), toxic epidermis detachment (TEN), eosinophilia and systemic syndrome (DRESS), or maculopapular rash (MPE) Associating as an increased risk of side effects of the drug being administered,
A method for assessing the risk that a patient will develop drug side effects (ADRs) induced by phenytoin.
The method according to claim 1, wherein detecting the presence of the HLA allele comprises using DNA prepared from the peripheral blood of the patient. A method to assess the risk of developing.
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