Pub Date : 2026-08-26DOI: 10.1038/s41397-026-00429-x
Kiflu Gebremicael Tesfamicael, Michael Musker, David L Adelson, Martin David Lewis
We developed an amplicon-based long-read sequencing approach that enables simultaneous detection of CYP2D6 single-nucleotide variants (SNVs) and copy-number variations (CNVs) in a single reaction. The SNVs of the two pseudogenes, CYP2D7 and CYP2D8, were also comprehensively characterized. CYP2D6 CNVs were inferred using CYP2D7 as a reference gene, integrating read-depth measurements with allele-frequency (AF) ratios. The entire CYP2D locus ( ~ 30.2Kb) and the three homologous genes separately (6.3-6.6Kb) were sequenced using Oxford Nanopore sequencing. Our analysis identified 21 CYP2D7 and 17 CYP2D8 unique haplotypes, and 57% of the SNVs detected in the pseudogenes had nucleotides corresponding to CYP2D6 reference nucleotides. A total of 36 variants found within the pseudogenes have also been annotated as functional variants in the CYP2D6 gene. The combined CYP2D6:CYP2D7 read-count ratio and reference-to-alternative alleles AF ratio accurately predicted CYP2D6 CNV status. This method is simple and rapid, making it potentially suitable for clinical implementation of pharmacogenomics.
{"title":"Amplicon-based long-read sequencing for accurate CYP2D6 gene deletion and duplication detection using CYP2D7 as a reference gene.","authors":"Kiflu Gebremicael Tesfamicael, Michael Musker, David L Adelson, Martin David Lewis","doi":"10.1038/s41397-026-00429-x","DOIUrl":"10.1038/s41397-026-00429-x","url":null,"abstract":"<p><p>We developed an amplicon-based long-read sequencing approach that enables simultaneous detection of CYP2D6 single-nucleotide variants (SNVs) and copy-number variations (CNVs) in a single reaction. The SNVs of the two pseudogenes, CYP2D7 and CYP2D8, were also comprehensively characterized. CYP2D6 CNVs were inferred using CYP2D7 as a reference gene, integrating read-depth measurements with allele-frequency (AF) ratios. The entire CYP2D locus ( ~ 30.2Kb) and the three homologous genes separately (6.3-6.6Kb) were sequenced using Oxford Nanopore sequencing. Our analysis identified 21 CYP2D7 and 17 CYP2D8 unique haplotypes, and 57% of the SNVs detected in the pseudogenes had nucleotides corresponding to CYP2D6 reference nucleotides. A total of 36 variants found within the pseudogenes have also been annotated as functional variants in the CYP2D6 gene. The combined CYP2D6:CYP2D7 read-count ratio and reference-to-alternative alleles AF ratio accurately predicted CYP2D6 CNV status. This method is simple and rapid, making it potentially suitable for clinical implementation of pharmacogenomics.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"26 5","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13518222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834705","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 : 2026-08-19DOI: 10.1038/s41397-026-00428-y
Aleksandra Petković Ćurčin, Aleksandra Jeremić, Danilo Joković, Gordana Šupić, Katarina Simić, Filip Milosavljević, Zvezdana Stojanović, Marin M Jukić
Cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme that influences antidepressant metabolism. This retrospective cohort study investigated the association between CYP2D6 genotype and treatment outcomes in 99 hospitalized patients with major depressive disorder (MDD) in Belgrade, Serbia. Patients were classified as poor (PM, n = 5), intermediate (IM, n = 21), or normal metabolizers (NM, n = 73). Effectiveness and tolerability were assessed from admission to discharge (~4 weeks). Hamilton Depression Rating Scale (HAM-D) score reduction was the primary outcome; tolerability was measured using the Toronto Side Effects Scale (TSES). Compared with NMs, HAM-D score reductions were 4.3 and 9.0 points lower in IMs and PMs. TSES scores were 1.3 and 2.3 points higher in IMs and PMs, respectively. Central nervous system and gastrointestinal effects were more frequent in IMs and PMs; sexual dysfunction did not differ. Reduced CYP2D6 activity was associated with poorer outcomes, indicating the potential usefulness of CYP2D6 genotyping in MDD.
细胞色素P450 2D6 （CYP2D6）是一种影响抗抑郁代谢的多态性酶。本回顾性队列研究调查了塞尔维亚贝尔格莱德99例重度抑郁症（MDD）住院患者CYP2D6基因型与治疗结果之间的关系。患者被分为代谢不良（PM, n = 5）、中度（IM, n = 21）和正常代谢（NM, n = 73）。从入院到出院（~4周）评估疗效和耐受性。汉密尔顿抑郁评定量表（HAM-D）得分降低是主要结局；使用多伦多副作用量表（TSES）测量耐受性。与NMs相比，IMs和pm的HAM-D评分降低了4.3分和9.0分。IMs和pm的TSES得分分别高出1.3和2.3分。中枢神经系统和胃肠道的影响在IMs和pm中更常见；性功能障碍没有差异。CYP2D6活性降低与较差的预后相关，表明CYP2D6基因分型在MDD中可能有用。
{"title":"Association between CYP2D6 genotype and treatment effectiveness and safety in 99 hospitalized patients with major depressive disorder a retrospective cohort study CYP2D6 genotype and antidepressant response.","authors":"Aleksandra Petković Ćurčin, Aleksandra Jeremić, Danilo Joković, Gordana Šupić, Katarina Simić, Filip Milosavljević, Zvezdana Stojanović, Marin M Jukić","doi":"10.1038/s41397-026-00428-y","DOIUrl":"https://doi.org/10.1038/s41397-026-00428-y","url":null,"abstract":"<p><p>Cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme that influences antidepressant metabolism. This retrospective cohort study investigated the association between CYP2D6 genotype and treatment outcomes in 99 hospitalized patients with major depressive disorder (MDD) in Belgrade, Serbia. Patients were classified as poor (PM, n = 5), intermediate (IM, n = 21), or normal metabolizers (NM, n = 73). Effectiveness and tolerability were assessed from admission to discharge (~4 weeks). Hamilton Depression Rating Scale (HAM-D) score reduction was the primary outcome; tolerability was measured using the Toronto Side Effects Scale (TSES). Compared with NMs, HAM-D score reductions were 4.3 and 9.0 points lower in IMs and PMs. TSES scores were 1.3 and 2.3 points higher in IMs and PMs, respectively. Central nervous system and gastrointestinal effects were more frequent in IMs and PMs; sexual dysfunction did not differ. Reduced CYP2D6 activity was associated with poorer outcomes, indicating the potential usefulness of CYP2D6 genotyping in MDD.</p>","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"26 5","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13489959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148801556","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 : 2026-08-05DOI: 10.1038/s41397-026-00424-2
Chris Eijsbouts, Yunxuan Jiang, James R. Ashenhurst, Julie M. Granka, 23andMe Research Team, Steven Pitts, Adam Auton, Noura S. Abul-Husn, Alison Chubb, R. Ryanne Wu
We evaluated the effect of CYP2C19 genotype on SSRI response in 114,627 research participants. We graded metabolizer status (0 for ultrarapid metabolizers to 4 for poor metabolizers), and regressed drug response outcomes on these grades. Among participants taking escitalopram or citalopram, slower metabolizers experienced side effects significantly more often than faster metabolizers (OR = 1.04 per grade, 95%CI = [1.02-1.06] and OR = 1.05 per grade, 95%CI = [1.02-1.07]) and were more likely to discontinue treatment due to side effects (OR = 1.05, 95%CI = [1.03-1.08], e.g. 29.7% of poor vs. 21.6% of ultrarapid metabolizers, and OR = 1.07, 95%CI = [1.04-1.11], e.g. 25.7% vs. 20.2%). Slower metabolizers taking escitalopram were more likely to suffer from sleep problems and sexual problems. Slower metabolizers taking sertraline reported tremor more often than faster metabolizers. Overall, we find substantial differences in side effect risk with different CYP2C19 genotypes, supporting the notion that individuals seeking depression treatment may benefit from pharmacogenetic-guided treatment selection to minimize side effects and reduce discontinuations.
{"title":"Large-scale analysis demonstrates the influence of CYP2C19 genotype on specific SSRI side effects","authors":"Chris Eijsbouts, Yunxuan Jiang, James R. Ashenhurst, Julie M. Granka, 23andMe Research Team, Steven Pitts, Adam Auton, Noura S. Abul-Husn, Alison Chubb, R. Ryanne Wu","doi":"10.1038/s41397-026-00424-2","DOIUrl":"10.1038/s41397-026-00424-2","url":null,"abstract":"We evaluated the effect of CYP2C19 genotype on SSRI response in 114,627 research participants. We graded metabolizer status (0 for ultrarapid metabolizers to 4 for poor metabolizers), and regressed drug response outcomes on these grades. Among participants taking escitalopram or citalopram, slower metabolizers experienced side effects significantly more often than faster metabolizers (OR = 1.04 per grade, 95%CI = [1.02-1.06] and OR = 1.05 per grade, 95%CI = [1.02-1.07]) and were more likely to discontinue treatment due to side effects (OR = 1.05, 95%CI = [1.03-1.08], e.g. 29.7% of poor vs. 21.6% of ultrarapid metabolizers, and OR = 1.07, 95%CI = [1.04-1.11], e.g. 25.7% vs. 20.2%). Slower metabolizers taking escitalopram were more likely to suffer from sleep problems and sexual problems. Slower metabolizers taking sertraline reported tremor more often than faster metabolizers. Overall, we find substantial differences in side effect risk with different CYP2C19 genotypes, supporting the notion that individuals seeking depression treatment may benefit from pharmacogenetic-guided treatment selection to minimize side effects and reduce discontinuations.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"26 4","pages":"32-"},"PeriodicalIF":2.8,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148681097","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}
Tacrolimus (TAC) exhibits substantial interindividual pharmacokinetic variability, complicating early dose optimization after kidney transplantation. This study evaluated the effects of CYP3A5 rs776746 (6986A > G), CYP3A4 rs4646437 (G > A), and ABCB1 rs1045642 (3435C > T) genetic variations on TAC metabolism during the first post-transplant month. In 120 kidney transplant recipients, TAC exposure was assessed using dose-normalized trough concentrations (C0/D), and patients with a low C0/D ratio (<1.05 ng/mL per mg/day) were classified as fast metabolizers, whereas those with a high C0/D ratio (≥1.05 ng/mL per mg/day) were classified as slow metabolizers. Fast metabolizers (48.3%) had lower TAC trough levels, required higher doses, and showed reduced C0/D ratios compared with slow metabolizers (0.95 ± 0.12 vs 2.39 ± 0.53 ng/mL per mg/day; p < 0.001). CYP3A5 rs776746 was the primary determinant, with each A allele strongly associated with fast metabolism (adjusted OR 44.11, 95% CI 11.70–166.36; p < 0.001). CYP3A4 rs4646437 provided additional stratification, whereas ABCB1 rs1045642 showed modest effects. Combined CYP3A5/CYP3A4 risk genotypes identified fast metabolizers in 88.2% of cases. These findings support genotype-informed TAC dosing to improve early post-transplant exposure.
{"title":"Effects of CYP3A4, CYP3A5, and ABCB1 genetic variants on tacrolimus metabolism during the early period after kidney transplantation","authors":"Nahathai Dukaew, Kajohnsak Noppakun, Mingkwan Na Takuathung, Nattharinee Kongta, Ratchanon Inpan, Naruemon Suyayai, Nut Koonrungsesomboon","doi":"10.1038/s41397-026-00427-z","DOIUrl":"10.1038/s41397-026-00427-z","url":null,"abstract":"Tacrolimus (TAC) exhibits substantial interindividual pharmacokinetic variability, complicating early dose optimization after kidney transplantation. This study evaluated the effects of CYP3A5 rs776746 (6986A > G), CYP3A4 rs4646437 (G > A), and ABCB1 rs1045642 (3435C > T) genetic variations on TAC metabolism during the first post-transplant month. In 120 kidney transplant recipients, TAC exposure was assessed using dose-normalized trough concentrations (C0/D), and patients with a low C0/D ratio (<1.05 ng/mL per mg/day) were classified as fast metabolizers, whereas those with a high C0/D ratio (≥1.05 ng/mL per mg/day) were classified as slow metabolizers. Fast metabolizers (48.3%) had lower TAC trough levels, required higher doses, and showed reduced C0/D ratios compared with slow metabolizers (0.95 ± 0.12 vs 2.39 ± 0.53 ng/mL per mg/day; p < 0.001). CYP3A5 rs776746 was the primary determinant, with each A allele strongly associated with fast metabolism (adjusted OR 44.11, 95% CI 11.70–166.36; p < 0.001). CYP3A4 rs4646437 provided additional stratification, whereas ABCB1 rs1045642 showed modest effects. Combined CYP3A5/CYP3A4 risk genotypes identified fast metabolizers in 88.2% of cases. These findings support genotype-informed TAC dosing to improve early post-transplant exposure.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"26 4","pages":"33-"},"PeriodicalIF":2.8,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148622468","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 : 2026-07-25DOI: 10.1038/s41397-026-00425-1
Amy Mathieson, Lisa Brunton, Stephanie Gillibrand, Ramona Moldovan, John H. McDermott
Direct-to-consumer (DTC) pharmacogenomic (PGx) testing is expanding rapidly in the UK, yet no dedicated regulatory framework currently governs these services. Although a 2021 parliamentary inquiry recommended stronger safeguards and clearer technical standards for genomic testing, these proposals have not been applied to PGx. This study explores public attitudes toward DTC PGx testing, focusing on expectations for pre-test information, quality standards, and NHS data use. We conducted focus groups with members of the public, both with and without prior experience of purchasing DTC PGx tests, or other online health tests. Focus groups were audio-recorded with consent, transcribed, and analysed thematically. We identified three themes: (mis)understanding towards and awareness of DTC PGx testing; altruistic motivation and equity concerns; and (mis)trust. Participants were generally enthusiastic about PGx testing, as long as issues of equity, data protection, and regulation were addressed, with data sharing concerns being particularly prominent.
{"title":"Understanding public perspectives on direct-to-consumer pharmacogenomic testing in the UK: a qualitative study","authors":"Amy Mathieson, Lisa Brunton, Stephanie Gillibrand, Ramona Moldovan, John H. McDermott","doi":"10.1038/s41397-026-00425-1","DOIUrl":"10.1038/s41397-026-00425-1","url":null,"abstract":"Direct-to-consumer (DTC) pharmacogenomic (PGx) testing is expanding rapidly in the UK, yet no dedicated regulatory framework currently governs these services. Although a 2021 parliamentary inquiry recommended stronger safeguards and clearer technical standards for genomic testing, these proposals have not been applied to PGx. This study explores public attitudes toward DTC PGx testing, focusing on expectations for pre-test information, quality standards, and NHS data use. We conducted focus groups with members of the public, both with and without prior experience of purchasing DTC PGx tests, or other online health tests. Focus groups were audio-recorded with consent, transcribed, and analysed thematically. We identified three themes: (mis)understanding towards and awareness of DTC PGx testing; altruistic motivation and equity concerns; and (mis)trust. Participants were generally enthusiastic about PGx testing, as long as issues of equity, data protection, and regulation were addressed, with data sharing concerns being particularly prominent.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"26 4","pages":"31-"},"PeriodicalIF":2.8,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148594635","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 : 2026-06-29DOI: 10.1038/s41397-026-00423-3
JM Rodríguez-Piñas, A. Romero-Lorca, A. Novillo, M. Gaibar, M. Rubio, B. Antón-Pascual, S. Hernando, I. Alemany, FI Camacho, M. Cavanagh, M. Boiza, D. Marrupe, AM Martín, R. Khedaoui, A. Fernández-Santander
The treatment of urothelial cancer (UC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICIs). However, while ICIs have achieved better therapeutic results than traditional chemotherapeutic agents, immune-related adverse events (irAEs) can lead to poor treatment outcomes. This exploratory study was designed to seek tumour single-nucleotide polymorphisms (SNPs) related to irAEs in patients with UC treated with ICIs. Tumour specimens were collected at several hospitals in Madrid (Spain) from 102 patients treated with nivolumab, atezolizumab, avelumab or pembrolizumab. DNA was extracted from formalin-fixed paraffin-embedded tumour biopsies, and 49 SNPs genotyped using a MassARRAY platform. Among the 49 SNPs analyzed, rs1738074 was associated both with overall toxicity (p < 0.001), and with the appearance of specific toxicities such as dermatitis and pneumonitis (p = 0.005 and p = 0.036, respectively). In effect, 100% of patients with pneumonitis were homozygous for the variant allele (p = 0.020). Other SNPs were also linked to a higher risk of irAEs: rs2301756 to pneumonitis (p = 0.005), rs55733913 and rs2117997 to dermatitis (p = 0.026, p = 0.021, respectively) and rs4988956 to hepatitis (p = 0.027). Contrarily, two SNPs, rs11571302 and rs66502444, showed a possible protective role against asthenia (p = 0.012, p = 0.030, respectively). This exploratory study highlights the possible useful role of tumour SNPs as biomarkers to predict the risk of UC patients developing irAEs. Further studies are needed to validate the utility of SNPs as biomarkers of ICI-induced toxicity.
{"title":"Toxicity related to immunotherapy in urothelial cancer: Tumour genetic risk variants","authors":"JM Rodríguez-Piñas, A. Romero-Lorca, A. Novillo, M. Gaibar, M. Rubio, B. Antón-Pascual, S. Hernando, I. Alemany, FI Camacho, M. Cavanagh, M. Boiza, D. Marrupe, AM Martín, R. Khedaoui, A. Fernández-Santander","doi":"10.1038/s41397-026-00423-3","DOIUrl":"10.1038/s41397-026-00423-3","url":null,"abstract":"The treatment of urothelial cancer (UC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICIs). However, while ICIs have achieved better therapeutic results than traditional chemotherapeutic agents, immune-related adverse events (irAEs) can lead to poor treatment outcomes. This exploratory study was designed to seek tumour single-nucleotide polymorphisms (SNPs) related to irAEs in patients with UC treated with ICIs. Tumour specimens were collected at several hospitals in Madrid (Spain) from 102 patients treated with nivolumab, atezolizumab, avelumab or pembrolizumab. DNA was extracted from formalin-fixed paraffin-embedded tumour biopsies, and 49 SNPs genotyped using a MassARRAY platform. Among the 49 SNPs analyzed, rs1738074 was associated both with overall toxicity (p < 0.001), and with the appearance of specific toxicities such as dermatitis and pneumonitis (p = 0.005 and p = 0.036, respectively). In effect, 100% of patients with pneumonitis were homozygous for the variant allele (p = 0.020). Other SNPs were also linked to a higher risk of irAEs: rs2301756 to pneumonitis (p = 0.005), rs55733913 and rs2117997 to dermatitis (p = 0.026, p = 0.021, respectively) and rs4988956 to hepatitis (p = 0.027). Contrarily, two SNPs, rs11571302 and rs66502444, showed a possible protective role against asthenia (p = 0.012, p = 0.030, respectively). This exploratory study highlights the possible useful role of tumour SNPs as biomarkers to predict the risk of UC patients developing irAEs. Further studies are needed to validate the utility of SNPs as biomarkers of ICI-induced toxicity.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"26 4","pages":"30-"},"PeriodicalIF":2.8,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13314534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148354399","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 : 2026-06-22DOI: 10.1038/s41397-026-00422-4
Mohamed A. Ismail
Maternal and neonatal health (MNH) urgently requires precision medicine interventions, as morbidity, mortality, and health disparities hinder the achievement of Sustainable Development Goal 3. Clinical implementation of artificial intelligence (AI)-powered Pharmacogenomics (PGx) requires validated, transparent algorithms and frameworks. The “pregnancy black box”-which refers to a data void due to historical exclusion of pregnant and postpartum women from clinical trials-continues to create bias in AI models. The review establishes a path for upcoming research, including methods to reduce algorithmic bias via AI-driven data augmentation, resolution of ethical challenges, and creation of international registries. Ultimately, leveraging AI for remote monitoring is crucial for enhancing equitable access in lower-resource environments. The proposed roadmap provides organizations with a robust framework to develop AI-driven PGx systems, which will enable safer and more tailored pharmacotherapy for mothers and their newborns.
{"title":"Beyond the ‘Pregnancy Black Box’: a global roadmap for artificial intelligence-driven pharmacogenomics in maternal-neonatal health","authors":"Mohamed A. Ismail","doi":"10.1038/s41397-026-00422-4","DOIUrl":"10.1038/s41397-026-00422-4","url":null,"abstract":"Maternal and neonatal health (MNH) urgently requires precision medicine interventions, as morbidity, mortality, and health disparities hinder the achievement of Sustainable Development Goal 3. Clinical implementation of artificial intelligence (AI)-powered Pharmacogenomics (PGx) requires validated, transparent algorithms and frameworks. The “pregnancy black box”-which refers to a data void due to historical exclusion of pregnant and postpartum women from clinical trials-continues to create bias in AI models. The review establishes a path for upcoming research, including methods to reduce algorithmic bias via AI-driven data augmentation, resolution of ethical challenges, and creation of international registries. Ultimately, leveraging AI for remote monitoring is crucial for enhancing equitable access in lower-resource environments. The proposed roadmap provides organizations with a robust framework to develop AI-driven PGx systems, which will enable safer and more tailored pharmacotherapy for mothers and their newborns.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"26 4","pages":"29-"},"PeriodicalIF":2.8,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13286999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148304020","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 : 2026-06-16DOI: 10.1038/s41397-026-00421-5
Birgit Deiman, Mike Hermans, Maarten de Rijk, Anne Bras, Volkher Scharnhorst
Clopidogrel therapy is recommended to prevent recurrent ischemic stroke. However, clopidogrel resistance exists. This study examines which enzymes are involved in clopidogrel resistance. The study group includes 402 neurology patients who had experienced a recurrent ischemic stroke while receiving clopidogrel monotherapy. Patients were genotyped for CYP2C19, CYP2C9, CYP2B6, CYP3A4, CYP3A5, CYP1A2, ABCB1 and CES1A1. Phenotype frequencies were compared with those of a Global(G), European(E) and a local patient control(C) group. Only for ABCB1 a significant difference in phenotype distribution was seen (pG = 0.003, pE = <0.001, pC = 0.019). In patient with ABCB1 rapid efflux activity (3435TT), no other enzyme was significantly associated. In patients with ABCB1 normal efflux activity (3435CT/CC), CYP2C19 intermediate and poor metabolism were significantly associated (pE = <0.001, pG = <0.001, pC = 0.002). In patients with normal CYP2C19 metabolism, CYP2C9 intermediate and poor metabolism were significantly associated (pG = <0.001, pE = <0.001, pC = <0.001). Besides CYP2C19 clinical guidelines, also for ABCB1 and CYP2C9 guidelines are needed to prevent clopidogrel resistance.
氯吡格雷被推荐用于预防缺血性卒中复发。然而，氯吡格雷耐药性是存在的。本研究探讨了哪些酶参与氯吡格雷耐药性。研究组包括402例在接受氯吡格雷单药治疗时经历过复发性缺血性中风的神经病学患者。对患者进行CYP2C19、CYP2C9、CYP2B6、CYP3A4、CYP3A5、CYP1A2、ABCB1和CES1A1基因分型。将表型频率与全球(G)、欧洲(E)和当地患者对照(C)组的表型频率进行比较。只有ABCB1在表型分布上有显著差异（pG = 0.003, pE = 0.003）
{"title":"The association of ABCB1, CYP2C19 and CYP2C9 combined activity with clopidogrel resistance in patients with recurrent ischemic stroke","authors":"Birgit Deiman, Mike Hermans, Maarten de Rijk, Anne Bras, Volkher Scharnhorst","doi":"10.1038/s41397-026-00421-5","DOIUrl":"10.1038/s41397-026-00421-5","url":null,"abstract":"Clopidogrel therapy is recommended to prevent recurrent ischemic stroke. However, clopidogrel resistance exists. This study examines which enzymes are involved in clopidogrel resistance. The study group includes 402 neurology patients who had experienced a recurrent ischemic stroke while receiving clopidogrel monotherapy. Patients were genotyped for CYP2C19, CYP2C9, CYP2B6, CYP3A4, CYP3A5, CYP1A2, ABCB1 and CES1A1. Phenotype frequencies were compared with those of a Global(G), European(E) and a local patient control(C) group. Only for ABCB1 a significant difference in phenotype distribution was seen (pG = 0.003, pE = <0.001, pC = 0.019). In patient with ABCB1 rapid efflux activity (3435TT), no other enzyme was significantly associated. In patients with ABCB1 normal efflux activity (3435CT/CC), CYP2C19 intermediate and poor metabolism were significantly associated (pE = <0.001, pG = <0.001, pC = 0.002). In patients with normal CYP2C19 metabolism, CYP2C9 intermediate and poor metabolism were significantly associated (pG = <0.001, pE = <0.001, pC = <0.001). Besides CYP2C19 clinical guidelines, also for ABCB1 and CYP2C9 guidelines are needed to prevent clopidogrel resistance.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"26 3","pages":"28-"},"PeriodicalIF":2.8,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41397-026-00421-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148267138","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 : 2026-06-13DOI: 10.1038/s41397-026-00418-0
Videha Sharma, John H. McDermott, Jessica Keen, Heidi Koikkalainen, Ian McNicoll, Angela Davies, William G. Newman
Pharmacogenetics uses genetic testing to improve the safety and effectiveness of prescribed medicines, yet implementation at scale remains limited due to the absence of interoperable health IT solutions that integrate results into prescribing workflows. This study aimed to develop and validate open data standards for pharmacogenetic results to enable interoperability across healthcare systems. A baseline data model was constructed using the open standard openEHR by synthesising literature, genomic sequencing outputs, and international data specifications, and refined through iterative workshops with the Global Alliance for Genomics and Health. The model underwent two rounds of structured peer review involving 24 experts from 10 countries. Mapping to HL7 FHIR was evaluated using both manual and automated approaches, including the FHIR-Connect tool. The resulting standardised pharmacogenetic data model separates test results from therapeutic implications and incorporates recognised terminologies such as SNOMED CT and HGNC. It achieved international consensus and is published on the openEHR Clinical Knowledge Manager platform. Mapping to HL7 FHIR demonstrated bidirectional information flow within healthcare systems, with automated mapping enabling scalable and reusable transformations. This work provides a framework for storing and exchanging pharmacogenetic test results, supporting semantic harmonisation, interoperability, and integration with clinical decision support systems. Open data standards for pharmacogenetic test results therefore offer a foundation for scalable implementation of pharmacogenetics in routine clinical practice.
{"title":"Development and validation of an open data model for pharmacogenetics to enable semantic interoperability in clinical practice","authors":"Videha Sharma, John H. McDermott, Jessica Keen, Heidi Koikkalainen, Ian McNicoll, Angela Davies, William G. Newman","doi":"10.1038/s41397-026-00418-0","DOIUrl":"10.1038/s41397-026-00418-0","url":null,"abstract":"Pharmacogenetics uses genetic testing to improve the safety and effectiveness of prescribed medicines, yet implementation at scale remains limited due to the absence of interoperable health IT solutions that integrate results into prescribing workflows. This study aimed to develop and validate open data standards for pharmacogenetic results to enable interoperability across healthcare systems. A baseline data model was constructed using the open standard openEHR by synthesising literature, genomic sequencing outputs, and international data specifications, and refined through iterative workshops with the Global Alliance for Genomics and Health. The model underwent two rounds of structured peer review involving 24 experts from 10 countries. Mapping to HL7 FHIR was evaluated using both manual and automated approaches, including the FHIR-Connect tool. The resulting standardised pharmacogenetic data model separates test results from therapeutic implications and incorporates recognised terminologies such as SNOMED CT and HGNC. It achieved international consensus and is published on the openEHR Clinical Knowledge Manager platform. Mapping to HL7 FHIR demonstrated bidirectional information flow within healthcare systems, with automated mapping enabling scalable and reusable transformations. This work provides a framework for storing and exchanging pharmacogenetic test results, supporting semantic harmonisation, interoperability, and integration with clinical decision support systems. Open data standards for pharmacogenetic test results therefore offer a foundation for scalable implementation of pharmacogenetics in routine clinical practice.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"26 3","pages":"27-"},"PeriodicalIF":2.8,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41397-026-00418-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148240313","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 : 2026-06-09DOI: 10.1038/s41397-026-00420-6
Carlos Perezcano, Mariana Pérez-Coria, Francisco Javier Borrayo-López
{"title":"Finasteride, pharmacogenomics, and suicide risk: a public health concern","authors":"Carlos Perezcano, Mariana Pérez-Coria, Francisco Javier Borrayo-López","doi":"10.1038/s41397-026-00420-6","DOIUrl":"10.1038/s41397-026-00420-6","url":null,"abstract":"","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"26 3","pages":"26-"},"PeriodicalIF":2.8,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213547","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}
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