Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity

Although trastuzumab‐induced cardiotoxicity is an important determinant to limit the use of this drug, the molecular mechanism of risk for this toxicity is not well understood. To identify genetic variants determining the risk of trastuzumab‐induced cardiotoxicity, we carried out whole exome sequencing of germline DNA samples from 9 patients with trastuzumab‐induced cardiotoxicity, and conducted a case‐control association study of 2258 genetic variants between 9 cases (with trastuzumab‐induced cardiotoxicity) and general Japanese population controls registered in the Human Genetic Variation Database (HGVD). The top variant which showed the lowest P‐value in the screening study was rs139503277 in PHD Finger Protein 3 (P_min = .00012, odds ratio [OR] = 51.23). To further validate the result of screening study, we carried out a replication study of 10 variants showing P_min < .001 in the screening study using 234 independent patients treated with trastuzumab, including 10 cases and 224 controls (without trastuzumab‐induced cardiotoxicity). In the replication study, we observed that three variants had an effect in the same direction as in the screening study (rs78272919 in exon 2 of Keratin 15, rs5762940 in exon 2 of zinc and ring finger 3, and rs139944387 in exon 44 of Eyes shut homologs [EYS]). A combined result of the screening and the replication studies suggested an association of a locus on chromosome 6q12 with trastuzumab‐induced cardiotoxicity (rs139944387 in EYS, combined P_min = .00056, OR = 13.73). This finding provides new insights into personalized trastuzumab therapy for patients with human epidermal growth factor receptor 2 (HER2)‐positive cancer.     

基于医药大数据建立精准药学临床评估体系的思考

目的：探讨医药大数据服务于精准药学的现有问题和对策。方法：通过文献资料,分析精准药学临床应用所需的大数据及其发展现状,从药物基因组学研究和个体基因组学研究的角度,探讨目前个体化用药研究的局限性。结果与结论：现有的药物基因组学研究成果远远不能满足临床需求,而基因组学研究成果过于碎片化,难以应用于临床。整合临床电子健康记录（EHR）的基因组研究,能反映药物研发和应用的实效;建立依据EHR和组学数据的精准药学临床评估体系,将大大提高精准药物研发和个体化用药的循证性和准确性。     

Identification of CYP2D6 null variants among long‐stay,chronic psychiatric inpatients: Is it strictly necessary?

We identified the null variants *3,*4,*5,*6,*7 and *8 of the CYP2D6 gene [encoding for cytochrome P450 (debrisoquine hydroxylase)] in a group of 84 chronic-stay psychiatric inpatients with severe schizophrenia or related disorders and receiving treatment with one or more CYP2D6 substrates for years. We also studied a group of 100 healthy controls of similar ethnic origin (Spanish Caucasians). Three patients were poor metabolizers (PMs) for antipsychotic drugs according to their CYP2D6 genotype (i.e. homozygous for the *4 allele) but they exhibited no adverse drug reaction over the years despite chronic treatment with CYP2D6 substrates. We suggest that CYP2D6 genetic screening is more useful in other type of psychiatric patients, particularly in younger ones starting treatment protocols.     

单核苷酸多态性研究及其对人类医学的影响

随着人类基因组序列测定的完成,基因组序列变异研究,特别是单核苷酸多态性(single nucleotide polymorphism,SNP)研究,成为新一轮基因组科学的研究重点,不断发展的高通量基因分型技术更使得人类对复杂性状疾病的理解和研究成为可能。由于SNP具有数量多、分布广、密度大、突变率低等特点,因此在人群多样性、疾病基因定位和药物基因组学的研究中都发挥了重要的作用。在此,本文尝试对目前国际上SNP计划的发展情况、以及在复杂疾病基因定位克隆研究和药物基因组学研究等方面的应用进行简要综述。     

肿瘤药物基因组学研究进展

药物基因组学对于解释药物反应的个体差异及开展个体化用药具有重要意义。近年来药物基因组学新技术在肿瘤药物治疗方面的进展和应用鉴定出多种影响肿瘤药物治疗的遗传变异,深刻影响肿瘤治疗的药物研发及个体化治疗。本文通过举例说明近期肿瘤药物基因组学重要研究进展的临床应用评价及面临的挑战,对肿瘤药物基因组学的发展及其临床应用进行综述。     

Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation

Background

Warfarin is a mainstay of therapy for conditions associated with an increased risk of thromboembolic events. However, the use of this common agent is fraught with complications and little is known regarding inter‐individual variation in warfarin response.

Objective

We tested for association between single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 and average weekly warfarin dose required to maintain patients at their desired anticoagulation target.

Methods

The sample consisted of 93 European‐American patients from anticoagulation clinics at the University of North Carolina at Chapel Hill. Data on mean weekly warfarin dose were collected over a mean treatment period of 20.6 months. ANCOVA models were used and haplotype analysis was performed.

Results

Three of six VKORC1 SNPs were found to be very strongly associated with the average warfarin dose required to achieve the target international normalised ratio (INR; p<0.0001). The mean weekly dose by genotype ranged from approximately 27 to 47 mg. There was no evidence for an association between either of the two CYP2C9 polymorphisms studied, CYP2C9*2 and CYP2C9*3. CYP2C9*3 was significantly (p = 0.05) associated with average warfarin dosage after adjustment for VKORC1*1173.

Conclusions

These results are of considerable clinical interest and confirm recently published results regarding the role of these two genes in modifying warfarin metabolism and maintenance dosage. The consistent findings regarding the role of VKORC1 and CYP2C9 in warfarin metabolism and maintenance dosage represent a clinically useful proof of principal for the use of pharmacogenomic information in medicine and may lead to improved understanding of warfarin''s actions.     

Identification of novel germline polymorphisms governing capecitabine sensitivity

BACKGROUND:

Capecitabine, an oral 5‐fluorouracil (5‐FU) prodrug, is widely used in the treatment of breast, colorectal, and gastric cancers. To guide the selection of patients with potentially the greatest benefit of experiencing antitumor efficacy, or, alternatively, of developing toxicities, identifying genomic predictors of capecitabine sensitivity could permit its more informed use.

METHODS:

The objective of this study was to perform capecitabine sensitivity genome‐wide association studies (GWAS) using 503 well genotyped human cell lines from individuals representing multiple different world populations. A meta‐analysis that included all ethnic populations then enabled the identification of novel germline determinants (single nucleotide polymorphisms [SNPs]) of capecitabine susceptibility.

RESULTS:

First, an intrapopulation GWAS of Caucasian individuals identified reference SNP 4702484 (rs4702484) (within adenylate cyclase 2 [ADCY2]) at a level reaching genome‐wide significance (P = 5.2 × 10^?8). This SNP is located upstream of the 5 methyltetrahydrofolate‐homocysteine methyltransferase reductase (MTRR) gene, and it is known that the enzyme for MTRR is involved in the methionine‐folate biosynthesis and metabolism pathway, which is the primary target of 5‐FU‐related compounds, although the authors were unable to identify a direct relation between rs4702484 and MTRR expression in a tested subset of cells. In the meta‐analysis, 4 SNPs comprised the top hits, which, again, included rs4702484 and 3 additional SNPs (rs8101143, rs576523, and rs361433) that approached genome‐wide significance (P values from 1.9 × 10^?7 to 8.8 × 10^?7). The meta‐analysis also identified 1 missense variant (rs11722476; serine to asparagine) within switch/sucrose nonfermentable‐related, matrix‐associated, actin‐dependent regulator of chromatin (SMARCAD1), a novel gene for association with capecitabine/5‐FU susceptibility.

CONCLUSIONS:

Toward the goal of individualizing cancer chemotherapy, the current study identified novel SNPs and genes associated with capecitabine sensitivity that are potentially informative and testable in any patient regardless of ethnicity. Cancer 2011. © 2011 American Cancer Society.     

Progress and prospects in pharmacogenetics of antidepressant drugs

Introduction: Depression is responsible for the most part of the personal and socio-economic burden due to psychiatric disorders. Since antidepressant response clusters in families, pharmacogenetics represents a meaningful tool to provide tailored treatments and improve the prognosis of depression.

Areas covered: This review aims to summarize and discuss the pharmacogenetics of antidepressant drugs in major depressive disorder, with a focus on the most replicated genes, genome-wide association studies (GWAS), but also on the findings provided by new and promising analysis methods. In particular, multimarker tests such as pathway analysis and polygenic risk scores increase the power of detecting associations compared to the analysis of individual polymorphisms. Since genetic variants are not necessarily associated with a change in protein level, gene expression studies may provide complementary information to genetic studies. Finally, the pharmacogenetic tests that have been investigated for clinical application are discussed.

Expert opinion: Despite the lack of widespread clinical applications, preliminary results suggest that pharmacogenetics may be useful to guide antidepressant treatment. The US Food and Drug Administration included pharmacogenetic indications in the labeling of several antidepressants. This represented an important official recognition of the clinical relevance of genetic polymorphisms in antidepressant treatment.