JP6143174B2 - Predictive test method for drug-induced proteinuria and human leukocyte antigen marker for predictive test - Google Patents
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Description
本発明は、薬剤誘発性蛋白尿を予測するための検査方法、及び、薬剤誘発性蛋白尿の予測検査のためのマーカーに関する。 The present invention relates to a test method for predicting drug-induced proteinuria and a marker for predictive test of drug-induced proteinuria.
関節リウマチ（RA：rheumatoid arthritis）は全身性の炎症性疾患で、関節の破壊を引き起こす。抗リウマチ薬には蛋白尿（腎障害の指標となる。）を起こす薬剤が多く知られており、関節リウマチの経過中に蛋白尿が認められることがある。蛋白尿は軽微なものからネフローゼを来たすものまであるが、組織にて糸球体へのアミロイド蛋白の沈着が高度な場合はより大量の蛋白尿を生じやすく、一方で、血管壁優位にアミロイドが沈着する場合は蛋白尿が軽微であっても腎機能低下が生じやすい。 Rheumatoid arthritis (RA) is a systemic inflammatory disease that causes joint destruction. Many antirheumatic drugs are known to cause proteinuria (which is an indicator of kidney damage), and proteinuria may be observed during the course of rheumatoid arthritis. Proteinuria ranges from mild to nephrotic, but if the tissue has a high level of amyloid protein deposition on the glomeruli, it tends to cause a larger amount of proteinuria, while amyloid deposits predominately on the vessel wall In this case, even if the proteinuria is slight, a decrease in renal function tends to occur.
血液中の蛋白が漏出すると、通常蛋白の50％以上を占めるアルブミンという蛋白が減少し、組織に余分な水分が残り、組織にあふれる状態であるむくみが発生する。また肺に余分な水分があふれると息苦しさが発生する。 When the protein in the blood leaks, the protein called albumin, which usually accounts for 50% or more of the protein, decreases, and excess moisture remains in the tissue, causing swelling that overflows the tissue. Also, if the lungs overflow with excess water, breathing difficulty will occur.
高頻度に蛋白尿をきたす抗リウマチ薬としては、例えば、ブシラミン(Bucillamine)、D-ペニシラミン(Penicillamine)、金チオリンゴ酸ナトリウム(Sodium Aurothiomalate)等が知られている。 As antirheumatic drugs that cause proteinuria with high frequency, for example, bucillamine (Bucillamine), D-penicillamine (Penicillamine), sodium sodium thiomalate (Sodium Aurothiomalate) and the like are known.
非特許文献１及び２には、ヨーロッパ系人種において、金チオリンゴ酸ナトリウム又はD-ペニシラミンによる蛋白尿発症のリスクと、HLA(ヒト白血球抗原)-DR3が関連することが記載されているが、その関連性の程度は十分なものとはいえない。 Non-Patent Documents 1 and 2 describe that in European races, the risk of proteinuria due to gold sodium thiomalate or D-penicillamine is related to HLA (human leukocyte antigen) -DR3. The degree of relevance is not sufficient.
本発明は、薬剤誘発性蛋白尿を的確に予測できる検査方法及びヒト白血球抗原マーカーを提供することを課題とする。 An object of the present invention is to provide a test method and a human leukocyte antigen marker capable of accurately predicting drug-induced proteinuria.
本発明にかかる薬剤誘発性蛋白尿を予測するための検査方法は、薬剤誘発性蛋白尿を予測するための検査方法であって、蛋白尿は、関節リウマチに対する薬剤であるブシラミン誘発性であり、ヒト白血球抗原であるHLA-DRB1*08:02又はDQB1*04:02を検出することを特徴とする。
The test method for predicting drug-induced proteinuria according to the present invention is a test method for predicting drug-induced proteinuria, and proteinuria is induced by bucillamine, which is a drug for rheumatoid arthritis, It is characterized by detecting human leukocyte antigen HLA-DRB1 * 08: 02 or DQB1 * 04: 02.
本発明にかかる薬剤誘発性蛋白尿の予測検査用ヒト白血球抗原マーカーは、薬剤誘発性蛋白尿の予測検査用ヒト白血球抗原マーカーであって、蛋白尿は、関節リウマチに対する薬剤であるブシラミン誘発性であり、HLA-DRB1*08:02又はDQB1*04:02からなることを特徴とする。
The human leukocyte antigen marker for predictive testing of drug-induced proteinuria according to the present invention is a human leukocyte antigen marker for predictive testing of drug-induced proteinuria, and proteinuria is induced by bucillamine, which is a drug for rheumatoid arthritis. Yes , consisting of HLA-DRB1 * 08: 02 or DQB1 * 04: 02.
本発明によれば、薬剤誘発性蛋白尿を的確に予測することができる。即ち、薬剤誘発性蛋白尿の発症可能性が高い患者を特定することができるので、本発明により特定された患者には、蛋白尿を誘発しにくい薬剤の投与や治療方針を選択し、決定する機会を得ることができる。 According to the present invention, drug-induced proteinuria can be accurately predicted. That is, since it is possible to identify a patient who is highly likely to develop drug-induced proteinuria, the patient identified by the present invention is selected and determined a drug administration or treatment policy that does not easily induce proteinuria. You can get an opportunity.
以下、本発明の実施形態について具体的に説明するが、当該実施形態は本発明の原理の理解を容易にするためのものであり、本発明の範囲は、下記の実施形態に限られるものではなく、当業者が以下の実施形態の構成を適宜置換した他の実施形態も、本発明の範囲に含まれる。
Hereinafter, embodiments of the present invention will be specifically described. However, the embodiments are for facilitating understanding of the principle of the present invention, and the scope of the present invention is not limited to the following embodiments. In addition, other embodiments in which those skilled in the art appropriately replace the configurations of the following embodiments are also included in the scope of the present invention.
本発明者らは、ヒト白血球抗原であるHLA-DRB1*08:02又はDQB1*04:02を検出することにより、薬剤誘発性蛋白尿を的確に予測できることを見いだして、この新知見に基づいて発明を完成させた。 The present inventors have found that drug-induced proteinuria can be accurately predicted by detecting human leukocyte antigen HLA-DRB1 * 08: 02 or DQB1 * 04: 02. Completed the invention.
本実施形態において蛋白尿を誘発させる薬剤は、特に限定されるものではないが、例えば、ブシラミン、金チオリンゴ酸ナトリウム、D-ペニシラミン等である。またこれら以外にも、例えば、メトトレキサート、ブシラミン、サラゾスルファピリジン、レフルノミド、タクロリムス、ミゾリビン、オーラノフィン、インフリキシマブ、エタネルセプト、アダリムマブ、トシリズマブ、アバタセプト、ゴリムマブ等についても、蛋白尿を誘発させる薬剤の対象とすることができる。 In the present embodiment, the drug that induces proteinuria is not particularly limited, and examples thereof include bucillamine, gold sodium thiomalate, D-penicillamine, and the like. In addition to these, for example, methotrexate, bucillamine, salazosulfapyridine, leflunomide, tacrolimus, mizoribine, auranofin, infliximab, etanercept, adalimumab, tocilizumab, abatacept, golimumab, etc. It can be.
本実施形態において、薬剤誘発性蛋白尿とは、薬剤により誘発される蛋白尿であればよく特に限定されないが、特に好ましくは、関節リウマチ（RA）患者における、薬剤により誘発される蛋白尿である。 In the present embodiment, the drug-induced proteinuria is not particularly limited as long as it is proteinuria induced by a drug, and is particularly preferably proteinuria induced by a drug in a patient with rheumatoid arthritis (RA). .
ヒトMHC分子であるHLA分子は、第６染色体短腕部の6p21.3の約4,000kbp内に存在するMHC領域によりコードされた遺伝子群に支配される遺伝子産物である。このMHC領域は、殆どの真核細胞膜表面上に表現されるHLA-A,B,C抗原系を支配するクラスI遺伝子領域と、B細胞やマクロファージ等の限定された組織あるいは細胞にしか表現されていない細胞特異的なHLA-DP,DQ,DR抗原系を支配するクラスII 遺伝子領域、および補体成分と21-ヒドロキシラーゼ等を支配するクラスIII遺伝子領域より構成されている。HLAクラスII分子は、MHCクラスII遺伝子領域にコードされる27kDaの膜結合型蛋白α鎖と、分子量34kDaの膜結合型蛋白β鎖とによって構成されている。クラスII分子β鎖は、遺伝的多型性に富むことが知られている。 The HLA molecule, which is a human MHC molecule, is a gene product controlled by a gene group encoded by the MHC region present within about 4,000 kbp of 6p21.3 of the short arm of chromosome 6. This MHC region is expressed only in the class I gene region that controls the HLA-A, B, and C antigen systems expressed on the surface of most eukaryotic cell membranes and in limited tissues or cells such as B cells and macrophages. It consists of a class II gene region that governs cell-specific HLA-DP, DQ, and DR antigen systems, and a class III gene region that governs complement components and 21-hydroxylase. The HLA class II molecule is composed of a 27 kDa membrane-bound protein α chain encoded by the MHC class II gene region and a membrane-bound protein β chain having a molecular weight of 34 kDa. Class II molecular β chains are known to be rich in genetic polymorphisms.
HLA-DRB1とDQB1の遺伝子座は、６番染色体上のすぐ近くに位置しており、強い連鎖不平衡にあるため、DRB1*08:02-DQB1*04:02のハプロタイプを形成している。このハプロタイプを持っていることは、薬剤誘発性蛋白尿の発症リスクに強い関連を有する。 The HLA-DRB1 and DQB1 loci are located in the immediate vicinity on chromosome 6 and are in a strong linkage disequilibrium, so they form a haplotype of DRB1 * 08: 02-DQB1 * 04: 02. Having this haplotype is strongly associated with the risk of developing drug-induced proteinuria.
本実施形態において、HLA-DRB1*08:02又はDQB1*04:02の検出方法は、自体公知の方法または今後開発されるあらゆる方法を適用することができる。例えば、HLA-DRB1*08:02又はDQB1*04:02を判別しうるDNA断片（特定DNA断片）をポリメラーゼ連鎖反応（PCR）により増幅し、得られたPCR産物を直接的に同定することで、検出することができる。このような方法による検出は、自体公知の市販の検出用キットを利用して行うことができる。 In this embodiment, as a method for detecting HLA-DRB1 * 08: 02 or DQB1 * 04: 02, a method known per se or any method developed in the future can be applied. For example, a DNA fragment (specific DNA fragment) that can distinguish HLA-DRB1 * 08: 02 or DQB1 * 04: 02 is amplified by polymerase chain reaction (PCR), and the resulting PCR product is directly identified. Can be detected. Detection by such a method can be performed using a commercially available detection kit known per se.
本発明の検査方法が適用される検体は、特に限定されるものではないが、例えばヒト由来の血液、尿、髄液、口腔粘膜等とすることができる。これら検体は、本実施形態の検査方法に適用されるとき、適当な緩衝液等で適宜希釈して使用することができる。例えば、PCR法を実施する場合、PCRを阻害する物質の影響を避けたり、低減化させることを目的として、適当な緩衝液で検体を適宜希釈して試料とすることが好ましい。ここにおいて、被検者より採取したものを検体といい、検査に供するために前処理したものを便宜上試料といい、それぞれ区別して用いられる。本実施形態の検査方法が適用される試料として、また、上記試料から調製した核酸試料を使用することもできる。核酸試料の調製は、自体公知の核酸調製法により実施することができる。核酸試料として、好ましくはゲノムDNAを用いる。調製した核酸は直接検出に使用してもよく、あるいは分析前に所望の領域をPCR又はその他の増幅法を用いることにより酵素的に増幅してもよい。 The specimen to which the test method of the present invention is applied is not particularly limited, and for example, human-derived blood, urine, spinal fluid, oral mucosa and the like can be used. When these specimens are applied to the test method of this embodiment, they can be used after appropriately diluted with an appropriate buffer or the like. For example, when the PCR method is carried out, it is preferable to prepare a sample by appropriately diluting a specimen with an appropriate buffer for the purpose of avoiding or reducing the influence of a substance that inhibits PCR. Here, the sample collected from the subject is referred to as a specimen, and the sample pretreated for use in the examination is referred to as a sample for the sake of convenience and is used separately. As a sample to which the inspection method of the present embodiment is applied, a nucleic acid sample prepared from the above sample can also be used. The nucleic acid sample can be prepared by a nucleic acid preparation method known per se. As the nucleic acid sample, preferably genomic DNA is used. The prepared nucleic acid may be used for direct detection or the desired region may be amplified enzymatically by using PCR or other amplification methods prior to analysis.
以下、実施例に基づいて本発明を詳細に説明する。本実施例の試験は、独立行政法人国立病院機構相模原病院の倫理委員会の承認を得て同院において遺伝子情報を扱う臨床研究として、「ヒトゲノム・遺伝子解析研究に関する倫理指針」および「臨床研究に関する倫理指針」を遵守して、行ったものである。 Hereinafter, the present invention will be described in detail based on examples. The test of this example was approved by the Ethics Committee of the National Hospital Organization Sagamihara Hospital as clinical research dealing with genetic information in the same hospital as “Ethical Guidelines for Human Genome / Gene Analysis Research” and “Ethics for Clinical Research”. This was done in compliance with the Guidelines.
本実施例では、各種HLAにつき、ブシラミン誘発性蛋白尿の既往のあるRA患者と、ブシラミン誘発性蛋白尿の既往のないRA患者とを比較することにより、ブシラミン誘発性蛋白尿への関連性を検討した。 In this example, for each type of HLA, by comparing RA patients with a history of bucillamine-induced proteinuria and RA patients without a history of bucillamine-induced proteinuria, the relationship to bucillamine-induced proteinuria was demonstrated. investigated.
白血球の抗原型は、WAKFlow(R) HLAタイピング試薬（Wakunaga）を用いて測定した。具体的には、RA患者より末梢静脈血約７mlを採取し、ゲノムDNAを抽出し、抽出したゲノムDNAからPCR-SSO法によりHLAをタイピングし、関連解析を行なった。 The leukocyte serotype was measured using WAKFlow® HLA typing reagent (Wakunaga). Specifically, about 7 ml of peripheral venous blood was collected from RA patients, genomic DNA was extracted, HLA was typed by PCR-SSO method from the extracted genomic DNA, and related analysis was performed.
下記表１に示すように、ブシラミン誘発性蛋白尿の既往のある日本人RA患者２５人と、ブシラミン誘発性蛋白尿の既往のない日本人RA患者４６０人とについて、調べた。 As shown in Table 1 below, 25 Japanese RA patients with a history of bucillamine-induced proteinuria and 460 Japanese RA patients with no history of bucillamine-induced proteinuria were examined.
既往のあるRA患者と、既往のないRA患者のブシラミンの平均服用量±SDはそれぞれ、150±68 mg/日、157±65 mg/日、ブシラミン投与の平均投与期間±SDはそれぞれ0.6±0.5年、2.4±3.2年であった。 The average doses of SD of bucillamine for patients with and without RA, 150 ± 68 mg / day, 157 ± 65 mg / day, respectively, and the average duration of treatment with bucillamine ± SD of 0.6 ± 0.5, respectively The year was 2.4 ± 3.2 years.
上記表１に示されるように、ブシラミンによる蛋白尿はHLA-DRB1*08:02とDQB1*04:02に強く関連することが新たに明らかになった。また、DRB1*08:02-DQB1*04:02 ハプロタイプ(P=7.65X10-7, オッズ比48.11, 95%信頼区間 11.17-207.12)にも強い関連を示した。 As shown in Table 1 above, it was newly clarified that proteinuria caused by bucillamine is strongly related to HLA-DRB1 * 08: 02 and DQB1 * 04: 02. It was also strongly related to DRB1 * 08: 02-DQB1 * 04: 02 haplotype (P = 7.65X10 -7 , odds ratio 48.11, 95% confidence interval 11.17-207.12).
これにより、HLA-DRB1*08:02又はDQB1*04:02をもつRA患者では、ブシラミン投与による薬剤誘発性蛋白尿を起こしやすいと考えられるところ、このような患者に対してはブシラミンの投与を控えることで、薬剤誘発性蛋白尿の発症を減少させることが可能になると考えられる。 As a result, in RA patients with HLA-DRB1 * 08: 02 or DQB1 * 04: 02, it is considered that drug-induced proteinuria is likely to occur due to bucillamine administration. By refraining, it is considered possible to reduce the onset of drug-induced proteinuria.
HLA-DRB1マーカーを用いたブシラミン誘発性蛋白尿の発症予測法の感度は28.0%、特異度は98.5%、陽性尤度比は18.4、陰性尤度比は0.731であった。ブシラミン誘発性蛋白尿の有病率は5.3%であるという報告(Nephron Clin Pract. 2006;104:c15)に基づくと、DRB1*08:02陽性例のリスクは50.5%に、陰性例では3.9%になると推測される。また、1例のブシラミン誘発性蛋白尿発症を防ぐためにスクリーニングをする必要がある症例数は74例となる。これは実用に耐える十分低い値であると考えられ、HLAマーカーを用いたブシラミン誘発性蛋白尿の発症予測法は薬剤選択の重要な情報となりうることが判明した。 The sensitivity of the onset prediction method for bucillamine-induced proteinuria using the HLA-DRB1 marker was 28.0%, specificity was 98.5%, positive likelihood ratio was 18.4, and negative likelihood ratio was 0.731. Based on a report that the prevalence of bucillamine-induced proteinuria is 5.3% (Nephron Clin Pract. 2006; 104: c15), the risk of DRB1 * 08: 02 positive cases is 50.5% and negative cases are 3.9% It is estimated that In addition, 74 cases need to be screened to prevent the onset of bucillamine-induced proteinuria. This is considered to be a sufficiently low value to withstand practical use, and it was found that the method of predicting the onset of bucillamine-induced proteinuria using HLA markers can be important information for drug selection.
なお、上記の実施例では薬剤としてブシラミンを使用した例を記載しているが、ブシラミンは、D-ペニシラミン及び金チオリンゴ酸ナトリウムとSH化合物である点において共通しており、また、ブシラミンは、D-ペニシラミン及び金チオリンゴ酸ナトリウムと慢性腎症を発症させる（参考文献：Am J Kidney Dis. 2002 Apr;39(4):706-12. Nagahama K, Matsushita H, Hara M, Ubara Y, Hara S, Yamada A. Bucillamine induces membranous glomerulonephritis. Adv Exp Med Biol. 1989;252:247-56. Hall CL. The natural course of gold and penicillamine nephropathy: a longterm study of 54 patients.）点においても共通している。そのため、HLA-DRB1*08:02又はDQB1*04:02をもつRA患者では、D-ペニシラミン又は金チオリンゴ酸ナトリウム投与によっても蛋白尿が誘発されると考えられる。 In addition, although the example which uses bucillamine as a chemical | medical agent is described in said Example, bucillamine is common in the point which is D-penicillamine and gold | metal sodium thiomalate, and SH compound, and bucillamine is D -Penicillamine and gold sodium thiomalate cause chronic nephropathy (reference: Am J Kidney Dis. 2002 Apr; 39 (4): 706-12. Nagahama K, Matsushita H, Hara M, Ubara Y, Hara S, Adv Exp Med Biol. 1989; 252: 247-56. Hall CL. The natural course of gold and penicillamine nephropathy: a longterm study of 54 patients. Therefore, in patients with RA with HLA-DRB1 * 08: 02 or DQB1 * 04: 02, proteinuria is also induced by administration of D-penicillamine or sodium gold thiomalate.
蛋白尿を誘発しにくい薬剤の投与や治療方針を選択する場合に有益である。 This is useful when selecting a drug administration or treatment strategy that does not easily induce proteinuria.
Claims (2)
蛋白尿は、関節リウマチに対する薬剤であるブシラミン誘発性であり、
ヒト白血球抗原であるHLA-DRB1*08:02又はDQB1*04:02を検出することを特徴とする、薬剤誘発性蛋白尿を予測するための検査方法。 A test method for predicting drug-induced proteinuria,
Proteinuria is induced by bucillamine, a drug for rheumatoid arthritis,
A test method for predicting drug-induced proteinuria, which comprises detecting human leukocyte antigen HLA-DRB1 * 08: 02 or DQB1 * 04: 02.
蛋白尿は、関節リウマチに対する薬剤であるブシラミン誘発性であり、
HLA-DRB1*08:02又はDQB1*04:02からなる薬剤誘発性蛋白尿の予測検査用ヒト白血球抗原マーカー。 A human leukocyte antigen marker for predictive testing of drug-induced proteinuria,
Proteinuria is induced by bucillamine, a drug for rheumatoid arthritis,
A human leukocyte antigen marker for predictive testing of drug-induced proteinuria consisting of HLA-DRB1 * 08: 02 or DQB1 * 04: 02.
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