Pharmacogenetics of glatiramer acetate therapy for multiple sclerosis reveals drug-response markers
Pharmacogenetics of glatiramer acetate therapy for multiple sclerosis reveals drug-response markers
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DOI：
10.1097/fpc.0b013e3281299169
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发表时间：
2007-08-01
影响因子：
2.6
通讯作者：
Miller, Ariel
中科院分区：
文献类型：
--
作者：
Grossman, Iris;Avidan, Nili;Miller, Ariel
基于遗传的治疗处方优化正在成为慢性疾病管理的中心研究焦点，如多发性硬化症，这会导致长期的药物方案调整。本研究的目的是确定遗传标记，可以预测醋酸格拉替雷（Copaxone）免疫治疗复发性多发性硬化症的反应。为此，我们对醋酸格拉替雷临床试验的两个部分队列的HLA-DRB 1 *1 501和61个单核苷酸多态性进行了基因分型，共27个候选基因。统计学分析包括单核苷酸多态性单核苷酸多态性和单倍型测试的药物治疗与安慰剂治疗groups.We报告检测醋酸格拉替雷反应和一个T细胞受体β（TRB@）变异重复在两个独立的队列（优势比=6.85）之间的统计学显着关联。在一个队列中，组织蛋白酶S（CTSS）基因的发现（P=0.049，经所有单核苷酸多态性和定义校正，比值比= 11.59）表明可能存在相关性，需要进一步研究。此外，我们记录了与其他五个基因MBP、CD 86、FAS、IL 1 R1和IL 12 RB 2的反应的名义上显著的关联，这些基因可能直接和间接地参与醋酸格拉替雷的作用模式。这些关联信号中的每一个本身都与无关联零假设一致，但是检测到的关联的数量维斯机会预期相比是令人惊讶的。此外，这些关联仅限于醋酸格拉替雷治疗组，而不是安慰剂组，清楚地表明了药物特异性遗传效应。这些发现为开发基于药物遗传学的多发性硬化症个性化治疗提供了额外的进展。
Genetic-based optimization of treatment prescription is becoming a central research focus in the management of chronic diseases, such as multiple sclerosis, which incur a prolonged drug-regimen adjustment. This study was aimed to identify genetic markers that can predict response to glatiramer acetate (Copaxone) immunotherapy for relapsing multiple sclerosis. For this purpose, we genotyped fractional cohorts of two glatiramer acetate clinical trials for HLA-DRB1*1 501 and 61 single nucleotide polymorphisms within a total of 27 candidate genes. Statistical analyses included single nucleotide polymorphism-by-single nucleotide polymorphism and haplotype tests of drug-by-genotype effects in drug-treated versus placebo-treated groups.We report the detection of a statistically significant association between glatiramer acetate response and a single nucleotide polymorphism in a T-cell receptor beta (TRB@) variant replicated in the two independent cohorts (odds ratio=6.85). Findings in the Cathepsin S (CTSS) gene (P=0.049 corrected for all single nucleotide polymorphisms and definitions tested, odds ratio = 11.59) in one of the cohorts indicate a possible association that needs to be further investigated. Additionally, we recorded nominally significant associations of response with five other genes, MBP, CD86, FAS, IL1R1 and IL12RB2, which are likely to be involved in glatiramer acetate's mode-of-action, both directly and indirectly. Each of these association signals in and of itself is consistent with the no-association null-hypothesis, but the number of detected associations is surprising vis-A-vis chance expectation. Moreover, the restriction of these associations to the glatiramer acetate-treated group, rather than the placebo group, clearly demonstrates drug-specific genetic effects. These findings provide additional progress toward development of pharmacogenetics-based personalized treatment for multiple sclerosis.