Genome-wide association studies of drug response and toxicity: an opportunity for genome medicine.
Genome-wide association studies of drug response and toxicity: an opportunity for genome medicine.
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DOI：
10.1038/nrd.2016.234
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发表时间：
2017-01
期刊：
影响因子：
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通讯作者：
Kubo M
中科院分区：
文献类型：
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作者：
Giacomini KM;Yee SW;Mushiroda T;Weinshilboum RM;Ratain MJ;Kubo M
不幸的是，有几个因素导致PGx研究中获得大样本集的挑战。对于大多数常见疾病的治疗，有许多药物可供使用;因此，使用特定药物的患者人数可能仅代表该特定疾病诊断患者的一小部分。此外，药物反应测量通常需要包括基线和治疗测量，以评估药物的效果，进一步限制了有资格获得PGx GWAS的患者数量。最后，需要对接受相同药物的患者进行相同药物反应测量的重复研究。从发生ADR的患者中获得足够数量的样本对PGx GWAS来说是一个更大的挑战，因为这些个体可能代表了使用特定药物的患者子集。在美国，这些问题在少数民族人口中被放大，其中人数已经低于欧洲血统的人口。因此，PGx GWAS要积累足够数量的样本，包括来自适当表征的复制组群、少数群体和ADR患者的样本，存在重大挑战。大型联合体加速PGx GWAS为了获得与药物反应表型相关的必要样本，类似于针对某些人类疾病建立的大型合作1，对于PGx GWAS的成功至关重要。事实上，已经建立了国际研究者联盟，重点关注几种药物（如华法林、他莫昔芬、选择性5-羟色胺再摄取抑制剂（SSRI）和二甲双胍）的PGx GWAS，并有助于确定接受这些药物的患者中疗效和毒性差异的遗传因素（表1）。PGx GWAS的药理学类别的最大子集代表抗癌药物疗法（图1d），其占迄今为止GWAS目录中报告的PGx研究的约25%。这些研究得到了美国国家癌症研究所（NCI）资助的肿瘤学临床试验的长期基础设施的促进，通常被称为“合作组”。通过NCI的癌症治疗评估计划（NCI-CTEP）协调，这些小组专注于FDA批准的常见恶性肿瘤（如乳腺癌、结直肠癌、肺癌和前列腺癌）的研究药物的III期研究。虽然合作小组促进了抗癌药物患者样本和表型信息的收集，但需要可靠的基因分型以及药理学和统计学方面的专业知识来优化这些研究。为此，一个名为PGRNRIKEN的大型国际财团于2008年成立，并继续作为美国国立卫生研究院（NIH）药物基因组学研究网络（PGRN）中心的一项活动。迄今为止，PGRNRIKEN已经进行了37个PGx GWAS，并且支持了GWAS目录中报告的最大数量的PGx研究：总共216个PGx GWAS中的16个（7.4%）（参见图1d）。
Unfortunately, there are several factors that contribute to the challenge of obtaining large sample sets in PGx research. For the treatment of most common diseases, many drugs are available; therefore, the number of patients on a particular drug probably only represents a fraction of patients with that specific disease diagnosis. In addition, drug response measurements frequently need to include both baseline and on-treatment measurements to assess the effect of the drug, further limiting the number of patients that qualify for a PGx GWAS. Finally, replication studies with the same drug response measurements need to be conducted on patients who receive the same drug. Obtaining an adequate number of samples from patients who have experienced an ADR represents an even greater challenge for PGx GWAS, as such individuals probably represent a subset of patients on a particular drug. In the United States, these issues are amplified for minority populations, in which numbers are already lower than for populations of European ancestry. Thus, there are substantial challenges for PGx GWAS to accrue sufficient numbers of samples, which include samples from appropriately characterized replication cohorts, minority populations and patients with ADRs.Large consortia accelerate PGx GWAS To obtain the necessary samples associated with drug response phenotypes, large collaborations, similar to those established for certain human diseases1, are crucial for the success of PGx GWAS. Indeed, international consortia of investigators focused on PGx GWAS of several drugs, such as warfarin, tamoxifen, selective serotonin reuptake inhibitors (SSRIs) and metformin, have been established and have contributed to the identification of the genetic factors that underlie variation in efficacy and toxicity among patients who receive these drugs (TABLE 1). The largest subset of the pharmacological classes of PGx GWAS represents anticancer drug therapies (FIG. 1d), which accounts for approximately 25% of PGx studies reported in the GWAS Catalog to date. Such studies have been facilitated by a long-standing infrastructure for oncology clinical trials funded by the US National Cancer Institute (NCI), generally referred to as the ‘cooperative groups’. Coordinated through the NCI’s Cancer Therapy Evaluation Program (NCI-CTEP), the groups focus on phase III studies of FDA-approved and investigational agents in common malignancies, such as breast, colorectal, lung and prostate cancer. Although the cooperative groups facilitate the collection of samples and phenotype information from patients on anticancer drugs, reliable genotyping, as well as expertise in pharmacology and statistics, is required to optimize these studies. To this end, a large international consortium named PGRNRIKEN was established in 2008 and continues as an activity of the US National Institutes of Health (NIH) Pharmacogenomics Research Network (PGRN) Hub. To date, PGRNRIKEN has conducted 37 PGx GWAS and has supported the largest number of PGx studies reported in the GWAS Catalog: 16 (7.4%) of 216 total PGx GWAS (see FIG. 1d).