Pub Date : 2022-02-11DOI: 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。
{"title":"UGT1A1 genetic variants are associated with increases in bilirubin levels in rheumatoid arthritis patients treated with sarilumab","authors":"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","doi":"10.1038/s41397-022-00269-5","DOIUrl":"10.1038/s41397-022-00269-5","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"22 3","pages":"160-165"},"PeriodicalIF":2.8,"publicationDate":"2022-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9151390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39607725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-31DOI: 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)。
{"title":"Evaluation of the EMPAR study population on the basis of metabolic phenotypes of selected pharmacogenes","authors":"Jochen Fracowiak, Tatjana Huebner, Steffen Heß, Christoph Roethlein, Daria Langner, Udo Schneider, Felix Falkenberg, Catharina Scholl, Roland Linder, Julia Stingl, Britta Haenisch, Michael Steffens","doi":"10.1038/s41397-022-00268-6","DOIUrl":"10.1038/s41397-022-00268-6","url":null,"abstract":"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).","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"22 2","pages":"136-144"},"PeriodicalIF":2.8,"publicationDate":"2022-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8975744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39876400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-31DOI: 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.
{"title":"Identification of sex-specific genetic associations in response to opioid analgesics in a White, non-Hispanic cohort from Southeast Minnesota","authors":"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","doi":"10.1038/s41397-022-00265-9","DOIUrl":"10.1038/s41397-022-00265-9","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"22 2","pages":"117-123"},"PeriodicalIF":2.8,"publicationDate":"2022-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8975736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39876401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-29DOI: 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.
{"title":"Impact of CYP2C19 metaboliser status on SSRI response: a retrospective study of 9500 participants of the Australian Genetics of Depression Study","authors":"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","doi":"10.1038/s41397-022-00267-7","DOIUrl":"10.1038/s41397-022-00267-7","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"22 2","pages":"130-135"},"PeriodicalIF":2.8,"publicationDate":"2022-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8975743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39960304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-22DOI: 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.
{"title":"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","authors":"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","doi":"10.1038/s41397-021-00263-3","DOIUrl":"10.1038/s41397-021-00263-3","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"22 2","pages":"109-116"},"PeriodicalIF":2.8,"publicationDate":"2022-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10689185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-17DOI: 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.
{"title":"Association of ITPA gene polymorphisms with adverse effects of AZA/6-MP administration: a systematic review and meta-analysis","authors":"Evaggelia Barba, Panagiota I. Kontou, Ioannis Michalopoulos, Pantelis G. Bagos, Georgia G. Braliou","doi":"10.1038/s41397-021-00255-3","DOIUrl":"10.1038/s41397-021-00255-3","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"22 1","pages":"39-54"},"PeriodicalIF":2.8,"publicationDate":"2022-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9242489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-21DOI: 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
{"title":"Correction to: PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors","authors":"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","doi":"10.1038/s41397-021-00264-2","DOIUrl":"10.1038/s41397-021-00264-2","url":null,"abstract":"","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"22 2","pages":"145-145"},"PeriodicalIF":2.8,"publicationDate":"2021-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41397-021-00264-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39858279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-11-25DOI: 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.
{"title":"Pharmacogenomic analysis of a genetically distinct Indigenous population","authors":"Arvind Jaya Shankar, Sudhir Jadhao, Wendy Hoy, Simon J. Foote, Hardip R. Patel, Vinod Scaria, Brendan J. McMorran, Shivashankar H. Nagaraj","doi":"10.1038/s41397-021-00262-4","DOIUrl":"10.1038/s41397-021-00262-4","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"22 2","pages":"100-108"},"PeriodicalIF":2.8,"publicationDate":"2021-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39660173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-11-13DOI: 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).
{"title":"PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors","authors":"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","doi":"10.1038/s41397-021-00261-5","DOIUrl":"10.1038/s41397-021-00261-5","url":null,"abstract":"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).","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"22 1","pages":"82-88"},"PeriodicalIF":2.8,"publicationDate":"2021-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10654775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-11-05DOI: 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.
{"title":"Application of long-read sequencing to elucidate complex pharmacogenomic regions: a proof of principle","authors":"Maaike van der Lee, William J. Rowell, Roberta Menafra, Henk-Jan Guchelaar, Jesse J. Swen, Seyed Yahya Anvar","doi":"10.1038/s41397-021-00259-z","DOIUrl":"10.1038/s41397-021-00259-z","url":null,"abstract":"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.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"22 1","pages":"75-81"},"PeriodicalIF":2.8,"publicationDate":"2021-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10649224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}