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UGT1A1 genetic variants are associated with increases in bilirubin levels in rheumatoid arthritis patients treated with sarilumab UGT1A1 基因变异与接受沙利鲁单抗治疗的类风湿性关节炎患者胆红素水平升高有关
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-02-11 DOI: 10.1038/s41397-022-00269-5
Nan Lin, Amy Damask, Anita Boyapati, Jennifer D. Hamilton, Sara Hamon, Nils Ternes, Michael C. Nivens, John Penn, Alexander Lopez, Jeffrey G. Reid, John Overton, Alan R. Shuldiner, Goncalo Abecasis, Aris Baras, Charles Paulding
Sarilumab is a human monoclonal antibody against interleukin (IL)-6Rα that has been approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) and an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). Mild liver function test abnormalities have been observed in patients treated with sarilumab. We describe a genome-wide association study of bilirubin elevations in RA patients treated with sarilumab. Array genotyping and exome sequencing were performed on DNA samples from 1075 patients. Variants in the UGT1A1 gene were strongly associated with maximum bilirubin elevations in sarilumab-treated patients (rs4148325; p = 2.88 × 10−41) but were not associated with aminotransferase elevations. No other independent loci showed evidence of association with bilirubin elevations after sarilumab treatment. These findings suggest that most bilirubin increases during sarilumab treatment are related to genetic variation in UGT1A1 rather than underlying liver injury.
沙利单抗是一种抗白细胞介素(IL)-6Rα的人类单克隆抗体,已被批准用于治疗中度至重度活动性类风湿性关节炎(RA)以及对一种或多种疾病修饰抗风湿药(DMARDs)反应不足或不耐受的成年患者。在接受萨利单抗治疗的患者中观察到了轻微的肝功能检测异常。我们描述了一项关于接受萨利单抗治疗的 RA 患者胆红素升高的全基因组关联研究。我们对 1075 例患者的 DNA 样本进行了阵列基因分型和外显子测序。UGT1A1基因中的变异与沙利鲁单抗治疗患者的胆红素最大值升高密切相关(rs4148325;p = 2.88 × 10-41),但与转氨酶升高无关。没有其他独立位点显示与沙利单抗治疗后胆红素升高有关。这些研究结果表明,沙利鲁单抗治疗期间胆红素升高大多与 UGT1A1 的遗传变异有关,而不是潜在的肝损伤。
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引用次数: 1
Evaluation of the EMPAR study population on the basis of metabolic phenotypes of selected pharmacogenes 根据选定药物基因的代谢表型评估 EMPAR 研究人群
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-01-31 DOI: 10.1038/s41397-022-00268-6
Jochen Fracowiak, Tatjana Huebner, Steffen Heß, Christoph Roethlein, Daria Langner, Udo Schneider, Felix Falkenberg, Catharina Scholl, Roland Linder, Julia Stingl, Britta Haenisch, Michael Steffens
The impact of genetic variability of pharmacogenes as a possible risk factor for adverse drug reactions is elucidated in the EMPAR (Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung/English: influence of metabolic profiles on the safety of drug therapy in routine care) study. EMPAR evaluates possible associations of pharmacogenetically predicted metabolic profiles relevant for the metabolism of frequently prescribed cardiovascular drugs. Based on a German study population of 10,748 participants providing access to healthcare claims data and DNA samples for pharmacogenetic assessment, first analyses were performed and evaluated. The aim of this first evaluation was the characterization of the study population with regard to general parameters such as age, gender, comorbidity, and polypharmacy at baseline (baseline year) as well as important combinations of cardiovascular drugs with relevant genetic variants and predicted metabolic phenotypes. The study was registered in the German Clinical Trials Register (DRKS) on July 6, 2018 (DRKS00013909).
EMPAR(Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung/英语:常规护理中代谢特征对药物治疗安全性的影响)研究阐明了药物基因的遗传变异作为药物不良反应的可能风险因素的影响。EMPAR 评估了药物基因预测代谢特征与常用心血管处方药代谢可能存在的关联。该研究以德国的 10748 名参与者为研究对象,这些参与者提供了医疗报销数据和用于药物基因评估的 DNA 样本,研究人员对这些数据进行了首次分析和评估。首次评估的目的是根据基线(基线年)时的年龄、性别、合并症、多重用药等一般参数,以及心血管药物的重要组合、相关基因变异和预测代谢表型,确定研究人群的特征。该研究于2018年7月6日在德国临床试验注册中心(DRKS)注册(DRKS00013909)。
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引用次数: 0
Identification of sex-specific genetic associations in response to opioid analgesics in a White, non-Hispanic cohort from Southeast Minnesota 明尼苏达州东南部非西班牙裔白人队列中阿片类镇痛药反应的性别特异性遗传关联鉴定
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-01-31 DOI: 10.1038/s41397-022-00265-9
Guilherme S. Lopes, Jaime L. Lopes, Suzette J. Bielinski, Sebastian M. Armasu, Ye Zhu, Dana C. Cavanaugh, Ann M. Moyer, Debra J. Jacobson, Liwei Wang, Ruoxiang Jiang, Jennifer L. St. Sauver, Nicholas B. Larson
The study of sex-specific genetic associations with opioid response may improve the understanding of inter-individual variability in pain treatments. We investigated sex-specific associations between genetic variation and opioid response. We identified participants in the RIGHT Study prescribed codeine, tramadol, hydrocodone, and oxycodone between 01/01/2005 and 12/31/2017. Prescriptions were collapsed into codeine/tramadol and hydrocodone/oxycodone. Outcomes included poor pain control and adverse reactions within six weeks after prescription date. We performed gene-level and single-variant association analyses stratified by sex. We included 7169 non-Hispanic white participants and a total of 1940 common and low-frequency variants (MAF > 0.01). Common variants in MACROD2 (rs76026520), CYP1B1 (rs1056837, rs1056836), and CYP2D6 (rs35742686) were associated with outcomes. At the gene level, FAAH, SCN1A, and TYMS had associations for men and women, and NAT2, CYP3A4, CYP1A2, and SLC22A2 had associations for men only. Our findings highlight the importance of considering sex in association studies on opioid response.
对阿片类药物反应的性别特异性遗传关联进行研究,可加深对疼痛治疗中个体间差异的理解。我们研究了基因变异与阿片类药物反应之间的性别特异性关联。我们确定了 RIGHT 研究的参与者在 2005 年 1 月 1 日至 2017 年 12 月 31 日期间开具的可待因、曲马多、氢可酮和羟考酮处方。处方分为可待因/曲马多和氢可酮/羟考酮。结果包括疼痛控制不佳和处方日期后六周内的不良反应。我们按性别进行了基因水平和单变体关联分析。我们纳入了 7169 名非西班牙裔白人参与者和共计 1940 个常见和低频变异(MAF > 0.01)。MACROD2(rs76026520)、CYP1B1(rs1056837、rs1056836)和 CYP2D6(rs35742686)中的常见变异与结果相关。在基因水平上,FAAH、SCN1A 和 TYMS 对男性和女性都有关联,而 NAT2、CYP3A4、CYP1A2 和 SLC22A2 仅对男性有关联。我们的研究结果凸显了在阿片类药物反应关联研究中考虑性别因素的重要性。
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引用次数: 4
Impact of CYP2C19 metaboliser status on SSRI response: a retrospective study of 9500 participants of the Australian Genetics of Depression Study CYP2C19 代谢状态对 SSRI 反应的影响:对 9500 名澳大利亚抑郁症遗传学研究参与者的回顾性研究
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-01-29 DOI: 10.1038/s41397-022-00267-7
Adrian I. Campos, Enda M. Byrne, Brittany L. Mitchell, Naomi R. Wray, Penelope A. Lind, Julio Licinio, Sarah E. Medland, Nicholas G. Martin, Ian B. Hickie, Miguel E. Rentería
Variation within the CYP2C19 gene has been linked to differential metabolism of selective serotonin reuptake inhibitors (SSRIs). Pharmacogenetic recommendations based on the effect of CYP2C19 variants have been made available and are used increasingly by clinical practitioners. Nonetheless, the underlying assumption linking differential metabolism to efficacy or adverse side effects remains understudied. Here, we aim to fill this gap by studying CYP2C19 polymorphisms and inferred metabolism and patient-reported antidepressant response in a sample of 9531 Australian adults who have taken SSRIs. Metaboliser status was inferred for participants based on CYP2C19 alleles. Primary analysis consisted of assessing differences in treatment efficacy and tolerability between normal (reference) and: ultrarapid, rapid, intermediate and poor metabolisers. Across medications, poor metabolisers reported a higher efficacy, whereas rapid metabolisers reported higher tolerability. When stratified by drug, associations between metaboliser status and efficacy did not survive multiple testing correction. Intermediate metabolisers were at greater odds of reporting any side effect for sertraline and higher number of side effects across medications and for sertraline. The effects between metaboliser status and treatment efficacy, tolerability and side effects were in the expected direction. Our power analysis suggests we would detect moderate to large effects, at least nominally. Reduced power may also be explained by heterogeneity in antidepressant dosages or concomitant medications, which we did not measure. The fact that we identify slower metabolisers to be at higher risk of side effects even without adjusting for clinical titration, and the nominally significant associations consistent with the expected metabolic effects provide new evidence for the link between CYP2C19 metabolism and SSRI response. Nonetheless, longitudinal and interventional designs such as randomized clinical trials that stratify by metaboliser status are necessary to establish the effects of CYP2C19 metabolism on SSRI treatment efficacy or adverse effects.
CYP2C19 基因的变异与选择性血清素再摄取抑制剂(SSRIs)的不同代谢有关。基于 CYP2C19 变异影响的药物遗传学建议已经问世,并被越来越多的临床医师采用。然而,将不同代谢与疗效或不良副作用联系起来的基本假设仍未得到充分研究。在此,我们以 9531 名服用过 SSRIs 的澳大利亚成年人为样本,研究他们的 CYP2C19 多态性和推断代谢以及患者报告的抗抑郁药反应,旨在填补这一空白。根据 CYP2C19 等位基因推断参与者的代谢状态。主要分析包括评估正常代谢者(参照)与超快速、快速、中等和不良代谢者之间在疗效和耐受性方面的差异。在所有药物中,代谢差者的疗效较高,而代谢快者的耐受性较高。如果按药物进行分层,代谢状态与疗效之间的联系经不起多重测试校正。中度代谢者报告舍曲林有任何副作用的几率更高,报告的各种药物和舍曲林副作用的次数也更多。代谢状态与疗效、耐受性和副作用之间的影响与预期方向一致。我们的功率分析表明,我们可以检测到中等至较大的效应,至少是名义上的效应。我们没有测量抗抑郁药剂量或同时服用药物的异质性,这也可能是导致功率下降的原因。即使不调整临床滴定,我们也发现代谢较慢的患者出现副作用的风险较高,而且名义上的显著关联与预期的代谢效应一致,这为CYP2C19代谢与SSRI反应之间的联系提供了新的证据。尽管如此,要确定CYP2C19代谢对SSRI疗效或不良反应的影响,还需要纵向和干预性设计,如按代谢状态分层的随机临床试验。
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引用次数: 13
A single nucleotide polymorphism-based formula to predict the risk of propofol TCI concentration being over 4 µg mL−1 at the time of loss of consciousness 基于单核苷酸多态性的公式预测意识丧失时丙泊酚 TCI 浓度超过 4 µg mL-1 的风险
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-01-22 DOI: 10.1038/s41397-021-00263-3
Zhuoling Zheng, Faling Xue, Haini Wang, Yongqi He, Lingyi Zhang, Wudi Ma, Caibin Zhang, Yanping Guan, Fang Ye, Yongzi Wen, Xiaoyan Li, Min Huang, Wenqi Huang, Zhongxing Wang, Jiali Li
We aim to develop a formula based on single nucleotide polymorphisms (SNPs) to predict whether the propofol target-controlled infusion (TCI) concentration would be over 4 μg mL−1 at the time of loss of consciousness (LOC). We recruited 184 patients undergoing thyroid or breast surgeries with propofol anaesthesia. A total of 48 SNPs of CYP2B6, CYP2C9, UGT1A9, HNF4A, ABCB1, ABCC4, ABCG2, GABRA2, GABRA4, GABRB1, GABRB3, GABRG2, GABBR2, GAD1, SLC1A3, BDNF, and NRXN1, previously associated with propofol metabolic and pharmacology pathway, were genotyped. The formula was developed in the training cohort using the least absolute shrinkage and selection operator logistic regression model, and then validated in the testing cohort. The SNPs, GABBR2 rs1167768, GABBR2 rs1571927, NRXN1 rs601010, BDNF rs2049046, GABRA4 rs1512135, UGT1A9 rs11692021, GABBR2 rs2808536, HNF4A rs1884613, GABRB3 rs2017247, and CYP2B6 rs3181842 were selected to construct the SNP-based formula, which was used to calculate the risk score for over 4 μg mL−1 TCI concentration of propofol at the time of LOC. Patients in the high-risk group were more likely to require a propofol concentration higher than 4 μg mL−1 and presented a longer LOC latency. The SNP-based formula may significantly improve the safety and effectiveness of propofol-induced anaesthesia.
我们旨在开发一种基于单核苷酸多态性(SNPs)的公式,用于预测意识丧失(LOC)时异丙酚靶控输注(TCI)浓度是否超过 4 μg mL-1。我们招募了 184 名接受甲状腺或乳腺手术并使用异丙酚麻醉的患者。我们对以前与异丙酚代谢和药理途径相关的 CYP2B6、CYP2C9、UGT1A9、HNF4A、ABCB1、ABCC4、ABCG2、GABRA2、GABRA4、GABRB1、GABRB3、GABRG2、GABBR2、GAD1、SLC1A3、BDNF 和 NRXN1 共 48 个 SNPs 进行了基因分型。利用最小绝对收缩和选择算子逻辑回归模型在训练队列中建立了公式,然后在测试队列中进行了验证。这些 SNPs 包括:GABBR2 rs1167768、GABBR2 rs1571927、NRXN1 rs601010、BDNF rs2049046、GABRA4 rs1512135、UGT1A9 rs11692021、GABBR2 rs2808536、HNF4A rs1884613、GABRB3 rs2017247、选择这些基因构建了基于 SNP 的公式,用于计算 LOC 时丙泊酚浓度超过 4 μg mL-1 TCI 的风险评分。高风险组患者更有可能需要使用浓度高于 4 μg mL-1 的异丙酚,并且 LOC 潜伏期更长。基于 SNP 的配方可大大提高异丙酚诱导麻醉的安全性和有效性。
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引用次数: 2
Association of ITPA gene polymorphisms with adverse effects of AZA/6-MP administration: a systematic review and meta-analysis ITPA 基因多态性与 AZA/6-MP 给药不良反应的关系:系统回顾和荟萃分析
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2022-01-17 DOI: 10.1038/s41397-021-00255-3
Evaggelia Barba, Panagiota I. Kontou, Ioannis Michalopoulos, Pantelis G. Bagos, Georgia G. Braliou
Azathioprine (AZA) and its metabolite, mercaptopurine (6-MP), are widely used immunosuppressant drugs. Polymorphisms in genes implicated in AZA/6-MP metabolism, reportedly, could account in part for their potential toxicity. In the present study we performed a systematic review and a meta-analysis, comprising 30 studies and 3582 individuals, to investigate the putative genetic association of two inosine triphosphatase (ITPA) polymorphisms with adverse effects in patients treated with AZA/6-MP. We found that rs1127354 is associated with neutropenia in general populations and in children (OR: 2.39, 95%CI: 1.97–2.90, and OR: 2.43, 95%CI: 2.12–2.79, respectively), and with all adverse effects tested herein in adult populations (OR: 2.12, 95%CI: 1.22–3.69). We also found that rs7270101 is associated with neutropenia and leucopenia in all-ages populations (OR: 2.93, 95%CI: 2.36–3.63, and OR: 2.82, 95%CI: 1.76–4.50, respectively) and with all adverse effects tested herein in children (OR: 1.74, 95%CI: 1.06–2.87). Stratification according to background disease, in combination with multiple comparisons corrections, verified neutropenia to be associated with both polymorphisms, in acute lymphoblastic leukemia (ALL) patients. These findings suggest that ITPA polymorphisms could be used as predictive biomarkers for adverse effects of thiopurine drugs to eliminate intolerance in ALL patients and clarify dosing in patients with different ITPA variants.
硫唑嘌呤(AZA)及其代谢产物巯基嘌呤(6-MP)是广泛使用的免疫抑制剂。据报道,与 AZA/6-MP 代谢有关的基因多态性可能是造成其潜在毒性的部分原因。在本研究中,我们对 30 项研究和 3582 人进行了系统回顾和荟萃分析,以调查两种肌苷三磷酸酶(ITPA)多态性与接受 AZA/6-MP 治疗的患者不良反应之间的假定遗传关联。我们发现,在普通人群和儿童中,rs1127354 与中性粒细胞减少症相关(OR:2.39,95%CI:1.97-2.90;OR:2.43,95%CI:2.12-2.79),在成人人群中,rs1127354 与本文测试的所有不良反应相关(OR:2.12,95%CI:1.22-3.69)。我们还发现,在所有年龄段人群中,rs7270101 与中性粒细胞减少症和白细胞减少症相关(OR:2.93,95%CI:2.36-3.63;OR:2.82,95%CI:1.76-4.50),在儿童中则与本文测试的所有不良反应相关(OR:1.74,95%CI:1.06-2.87)。在急性淋巴细胞白血病(ALL)患者中,根据背景疾病进行分层并结合多重比较校正,证实了中性粒细胞减少与这两种多态性有关。这些研究结果表明,ITPA多态性可作为硫嘌呤类药物不良反应的预测性生物标记物,以消除ALL患者的不耐受性,并明确不同ITPA变体患者的用药剂量。
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引用次数: 7
Correction to: PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors 更正为血管内皮生长因子通路抑制剂诱发高血压的 PIK3R5 遗传预测因素
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2021-12-21 DOI: 10.1038/s41397-021-00264-2
Julia C. F. Quintanilha, Alessandro Racioppi, Jin Wang, Amy S. Etheridge, Stefanie Denning, Carol E. Peña, Andrew D. Skol, Daniel J. Crona, Danyu Lin, Federico Innocenti
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引用次数: 0
Pharmacogenomic analysis of a genetically distinct Indigenous population 对基因独特的土著人群进行药物基因组学分析
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2021-11-25 DOI: 10.1038/s41397-021-00262-4
Arvind Jaya Shankar, Sudhir Jadhao, Wendy Hoy, Simon J. Foote, Hardip R. Patel, Vinod Scaria, Brendan J. McMorran, Shivashankar H. Nagaraj
Indigenous Australians face a disproportionately severe burden of chronic disease relative to other Australians, with elevated rates of morbidity and mortality. While genomics technologies are slowly gaining momentum in personalised treatments for many, a lack of pharmacogenomic research in Indigenous peoples could delay adoption. Appropriately implementing pharmacogenomics in clinical care necessitates an understanding of the frequencies of pharmacologically relevant genetic variants within Indigenous populations. We analysed whole-genome sequence data from 187 individuals from the Tiwi Islands and characterised the pharmacogenomic landscape of this population. Specifically, we compared variant profiles and allelic distributions of previously described pharmacologically significant genes and variants with other population groups. We identified 22 translationally relevant pharmacogenomic variants and 18 clinically actionable guidelines with implications for drug dosing and treatment of conditions including heart disease, diabetes and cancer. We specifically observed increased poor and intermediate metabolizer phenotypes in the CYP2C9 (PM:19%, IM:44%) and CYP2C19 (PM:18%, IM:44%) genes.
与其他澳大利亚人相比,澳大利亚原住民面临着不成比例的严重慢性疾病负担,发病率和死亡率都很高。虽然基因组学技术在为许多人提供个性化治疗方面的发展势头缓慢,但缺乏针对土著居民的药物基因组学研究可能会延误该技术的应用。要在临床治疗中适当实施药物基因组学,就必须了解土著居民中与药物相关的基因变异的频率。我们分析了来自蒂维群岛(Tiwi Islands)187 人的全基因组序列数据,并描述了这一人群的药物基因组学特征。具体来说,我们将以前描述过的具有药理学意义的基因和变体的变异情况和等位基因分布与其他人群进行了比较。我们发现了 22 个具有转化意义的药物基因组变异和 18 个具有临床可操作性的指南,这些指南对药物剂量以及心脏病、糖尿病和癌症等疾病的治疗具有重要意义。我们特别观察到 CYP2C9(PM:19%,IM:44%)和 CYP2C19(PM:18%,IM:44%)基因中不良和中间代谢表型的增加。
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引用次数: 4
PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors 血管内皮生长因子通路抑制剂诱发高血压的 PIK3R5 遗传预测因子
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2021-11-13 DOI: 10.1038/s41397-021-00261-5
Julia C. F. Quintanilha, Alessandro Racioppi, Jin Wang, Amy S. Etheridge, Stefanie Denning, Carol E. Peña, Andrew D. Skol, Daniel J. Crona, Danyu Lin, Federico Innocenti
No biomarkers are available to predict patients at risk of developing hypertension induced by VEGF-pathway inhibitors. This study aimed to identify predictive biomarkers of hypertension induced by these drugs using a discovery-replication approach. The discovery set included 140 sorafenib-treated patients (TARGET study) genotyped for 973 SNPs in 56 genes. The most statistically significant SNPs associated with grade ≥2 hypertension were tested for association with grade ≥2 hypertension in the replication set of a GWAS of 1039 bevacizumab-treated patients from four clinical trials (CALGB/Alliance). In the discovery set, rs444904 (G > A) in PIK3R5 was associated with an increased risk of sorafenib-induced hypertension (p = 0.006, OR = 3.88 95% CI 1.54–9.81). In the replication set, rs427554 (G > A) in PIK3R5 (in complete linkage disequilibrium with rs444904) was associated with an increased risk of bevacizumab-induced hypertension (p = 0.008, OR = 1.39, 95% CI 1.09–1.78). This study identified a predictive marker of drug-induced hypertension that should be evaluated for other VEGF-pathway inhibitors. ClinicalTrials.gov Identifier:NCT00073307 (TARGET).
目前还没有生物标志物来预测血管内皮生长因子途径抑制剂诱发高血压的风险。本研究采用发现-复制的方法,旨在确定这些药物诱发高血压的预测性生物标志物。发现集包括 140 例索拉非尼治疗患者(TARGET 研究),对 56 个基因中的 973 个 SNP 进行了基因分型。在对来自四项临床试验(CALGB/Alliance)的 1039 名贝伐珠单抗治疗患者进行的 GWAS 复制集中,检测了与≥2 级高血压相关的最具统计学意义的 SNPs。在发现集中,PIK3R5中的rs444904(G >A)与索拉非尼诱发的高血压风险增加有关(p = 0.006,OR = 3.88 95% CI 1.54-9.81)。在复制集中,PIK3R5中的rs427554(G >A)(与rs444904完全连锁不平衡)与贝伐珠单抗诱发高血压的风险增加有关(p = 0.008,OR = 1.39,95% CI 1.09-1.78)。这项研究发现了药物诱发高血压的预测标志物,应该对其他血管内皮生长因子途径抑制剂进行评估。ClinicalTrials.gov Identifier:NCT00073307 (TARGET)。
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引用次数: 2
Application of long-read sequencing to elucidate complex pharmacogenomic regions: a proof of principle 应用长序列测序阐明复杂的药物基因组区域:原理验证
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2021-11-05 DOI: 10.1038/s41397-021-00259-z
Maaike van der Lee, William J. Rowell, Roberta Menafra, Henk-Jan Guchelaar, Jesse J. Swen, Seyed Yahya Anvar
The use of pharmacogenomics in clinical practice is becoming standard of care. However, due to the complex genetic makeup of pharmacogenes, not all genetic variation is currently accounted for. Here, we show the utility of long-read sequencing to resolve complex pharmacogenes by analyzing a well-characterised sample. This data consists of long reads that were processed to resolve phased haploblocks. 73% of pharmacogenes were fully covered in one phased haploblock, including 9/15 genes that are 100% complex. Variant calling accuracy in the pharmacogenes was high, with 99.8% recall and 100% precision for SNVs and 98.7% precision and 98.0% recall for Indels. For the majority of gene-drug interactions in the DPWG and CPIC guidelines, the associated genes could be fully resolved (62% and 63% respectively). Together, these findings suggest that long-read sequencing data offers promising opportunities in elucidating complex pharmacogenes and haplotype phasing while maintaining accurate variant calling.
药物基因组学在临床实践中的应用正逐渐成为护理标准。然而,由于药物基因的遗传结构复杂,目前并没有考虑到所有的遗传变异。在这里,我们通过分析一个特征良好的样本,展示了长读数测序在解析复杂药物基因方面的效用。该数据由长读数组成,经过处理后可解析相位单倍群。73%的药物基因被完全覆盖在一个阶段性单倍区块中,包括9/15个100%复杂的基因。药物基因的变异调用准确率很高,SNV 的召回率为 99.8%,准确率为 100%;Indels 的准确率为 98.7%,召回率为 98.0%。对于 DPWG 和 CPIC 指南中的大多数基因-药物相互作用,相关基因可以完全解析(分别为 62% 和 63%)。这些发现共同表明,长读程测序数据为阐明复杂的药物基因和单体型分期提供了大有可为的机会,同时还能保持变异调用的准确性。
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引用次数: 9
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Pharmacogenomics Journal
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