Application of pharmacogenetic/pharmacogenomic data to personalize treatment in routine clinical practice. A narrative review. / Aplicación de datos farmacogenéticos/farmacogenómicos para personalizar el tratamiento en la práctica clínica habitual. Revisión narrativa.

OBJECTIVE: The aim of this article is to perform a narrative review of how pharmacogenetics and pharmacogenomics is being applied in the clinic, especially in Spain. METHOD: Publications and websites of major interest have been reviewed. RESULTS: Pharmacogenes and variants used in several hospitals, available methodologies, and the implementation process are discussed.

[Translated article] Application of pharmacogenetic/pharmacogenomic data to personalise treatment in routine clinical practice. A narrative review.

OBJECTIVE: The aim of this article was to perform a narrative review of how pharmacogenetics and pharmacogenomics is being applied in the clinics, especially in Spain. METHOD: Publications and websites of major interest have been reviewed. RESULTS: Pharmacogenes and variants used in several hospitals, available methodologies, and the implementation process are discussed.

Efficacy and adverse reactions of donepezil:a pharmacogenomic study / 中华老年心脑血管病杂志

Objective To analyze the efficacy and adverse reactions of donepezil in the treatment of patients with a continuous disease spectrum of Alzheimer's disease(AD)with pharmacogenomics.Methods Seventy-two patients who took donepezil therapy at the time of initial molecular pa-thology diagnosis of AD continuous disease spectrum in Chinese PLA General Hospital from Jan-uary 2022 to January 2023 were recruited.Cells from the oral buccal mucosa were collected,and MassARRAY nucleic acid mass spectrometry was applied to detect the genotypes of CYP2D6,the gene encoding cytochrome P450 2D6 enzyme,and CHAT,the gene encoding acetylcholine trans-ferase.After 9 months of follow-up,drug efficacy was indirectly determined by neurological func-tion scales,caregiver evaluations,and drug prescribing behaviors,and thus,the 50 patients on donepezil alone were divide into effective group(n=28)and ineffective group(n=22).Seventy-two patients were divided into adverse reaction group(n=12)and no adverse reaction group(n=60).Multivariate logistic regression analysis was used to analyze the correlation between donepezil efficacy and pharmacogenomics.Results The frequencies of CHAT rs3793790 locus carrying G allele and rs2177370 locus carrying A allele were significantly higher in the effective group than the ineffective group(35.71％vs 9.09％,P=0.029;42.86％vs 9.09％,P=0.008).Multivariate lo-gistic regression analysis showed that donepezil was more effective in those who carrying rs3793790 G allele and/or rs2177370 A allele in the CHAT gene than those who carrying neither of the alleles(95％CI:1.20-34.47,P=0.030).There were no statistical differences in the CYP2D6 gene-adjusted activity score and whether or not carrying*10 between the patients with and without adverse reactions(P＞0.0 5).Conclusion In patients with a continuous spectrum of AD,donepezil efficacy is associated with CHAT gene polymorphisms,but there is no correlation between donepezil adverse reactions and CYP2D6 genotype.

DRD2, DRD3, and HTR2A Single-Nucleotide Polymorphisms Involvement in High Treatment Resistance to Atypical Antipsychotic Drugs.

BACKGROUND: The objective of this study was to investigate the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, and rs6311 single-nucleotide polymorphism (SNP) correlations with resistance to second-generation antipsychotics (SGAs) in a real-world sample of patients with treatment-resistant mental disorders. METHODS: We divided 129 participants into a high treatment resistance (HTR) group (current treatment with two SGAs, or clozapine, or classic neuroleptics for a failure of previous SGAs trials) and a low treatment resistance (LTR) group (current treatment with one atypical antipsychotic). We used Next-Generation Sequencing on DNA isolated from peripheral blood samples to analyze the polymorphisms. We performed logistic regression to search for predictors of HTR membership. RESULTS: A diagnosis of schizophrenia significantly predicted the HTR membership compared to other diagnoses. Other predictors were the DRD3 rs6280 C|T (OR = 22.195) and T|T (OR = 18.47) vs. C|C, HTR2A rs7997012 A|G vs. A|A (OR = 6.859) and vs. G|G (OR = 2.879), and DRD2 rs1799732 I|I vs. D|I (OR = 12.079) genotypes. CONCLUSIONS: A diagnosis of schizophrenia and the DRD2 rs1799732, DRD3 rs6280, and HTR2A rs7997012 genotypes can predict high treatment resistance to SGAs.

Genetic Variants Associated with Drug Resistance of Cytomegalovirus in Hematopoietic Cell Transplantation Recipients.

Cytomegalovirus (CMV) infection is a serious complication in hematopoietic cell transplantation (HCT) recipients. Drug-resistant strains make it more challenging to treat CMV infection. This study aimed to identify variants associated with CMV drug resistance in HCT recipients and assess their clinical significance. A total of 123 patients with refractory CMV DNAemia out of 2271 HCT patients at the Catholic Hematology Hospital between April 2016 and November 2021 were analyzed, which accounted for 8.6% of the 1428 patients who received pre-emptive therapy. Real-time PCR was used to monitor CMV infection. Direct sequencing was performed to identify drug-resistant variants in UL97 and UL54. Resistance variants were found in 10 (8.1%) patients, and variants of uncertain significance (VUS) were found in 48 (39.0%) patients. Patients with resistance variants had a significantly higher peak CMV viral load than those without (p = 0.015). Patients with any variants had a higher risk of severe graft-versus-host disease and lower one-year survival rates than those without (p = 0.003 and p = 0.044, respectively). Interestingly, the presence of variants reduced the rate of CMV clearance, particularly in patients who did not modify their initial antiviral regimen. However, it had no apparent impact on individuals whose antiviral regimens were changed due to refractoriness. This study highlights the importance of identifying genetic variants associated with CMV drug resistance in HCT recipients for providing appropriate antiviral treatment and predicting patient outcomes.

Pharmacogenomics and beyond! Customized pharmacotherapy for solid organ transplant recipients.

Solid organ transplant recipients are reliant on immunosuppressive drugs, which have a narrow therapeutic index, and are concurrently vulnerable to adverse drug events due to comorbidity burden and the complexity of their medication regimens. Urgent management of post-transplant complications often falls to the generalist clinician or critical care specialist. The purpose of this narrative review is to discuss innovations and bedside applications of pharmacogenomics and therapeutic drug monitoring applied to immunosuppression and agents frequently encountered in transplant recipients. Medication formulations will be given specific attention, as interchange is frequently required in the acute care setting. Bioassays quantifying immune system activity will be described with practical applications. A structured approach to addressing drug-drug, drug-gene, and drug-drug-gene interactions will be modeled using a case-based approach synthesizing pharmacogenomics, therapeutic drug monitoring, pharmacokinetics, and pharmacodynamic principles.

The role of CYP2C9*2, CYP2C9*3 and VKORC1-1639 variants on the susceptibility of upper gastrointestinal bleeding: A full case-control study.

Purpose: To investigate whether interindividual variability in the CYP2C9 (*2 and *3 alleles) and VKORC1 (rs9923231) genes is associated with increased risk of upper gastrointestinal bleeding (UGIB) in users of non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA). Methods: A full case-control study including 200 cases of patients diagnosed with UGIB and 706 controls was conducted in a Brazilian hospital complex. To perform an analysis of NSAIDs dose-effect, the defined daily dose (DDD) for NSAIDs was calculated in the 7-day etiologic window preceding the data index. Three categories of DDD, considering the genotypes of the genetic variants, were established: non-users of NSAIDs (DDD = 0), DDD ≤0.5, and DDD >0.5. Genetic variants and LDA or NSAIDs use synergism was estimated through Synergism Index (SI) and Relative Excess Risk Due To Interaction (RERI). Results: For DDDs of NSAIDs upward of 0.50, a risk of UGIB was identified in carriers of the *3 allele (OR: 15,650, 95% CI: 1.41-174.10) and in carriers of the variant homozygous genotype (TT) of rs9923231 (OR: 38,850, 95% CI: 2.70-556.00). In LDA users, the risk of UGIB was observed to be similar between carriers of the wild type homozygous genotype and carriers of the variant alleles for the CYP2C9 and VKORC1 genes. No synergism was identified. Conclusion: Our findings suggest an increased risk of UGIB in carriers of the variant allele of rs9923231 and in carriers of the *3 allele associated with doses of NSAIDs greater than 0.5. Hence, the assessment of these variants might reduce the incidence of NSAIDs-related UGIB and contribute to the safety of the NSAIDs user.

Pharmacogenetics of CYP2A6, CYP2B6, and UGT2B7 in the Context of HIV Treatments in African Populations.

OBJECTIVES: This study focuses on identifying variations in selected CYP genes related to treatment responses in patients with HIV in African populations by investigating variant characteristics and effects in African cohorts. DESIGN: Cytochrome P450 (CYP) 2A6, 2B6, and Uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B7 allele frequencies were studied using public-domain datasets obtained from the 1000 Genomes Phase 3 project, the African Genome Variation Project (AGVP), and the South African Human Genome Programme (SAHGP). METHODS: Variant annotations were performed using self-identified ethnicities to conduct allele frequency analysis in a population-stratification-sensitive manner. The NCBI DB-SNP database was used to identify documented variants and standard frequencies, and the E! Ensembl Variant Effect Predictor tool was used to perform the prediction of possible deleterious variants. RESULTS: A total of 4468 variants were identified across 3676 individuals following pre-filtering. Seventy-one variants were identified at an allelic frequency (1% or more in at least one population), which were predicted to be linked to existing disease associations and, in some cases, linked to drug metabolisms. This list was further studied to identify 23 alleles with disease considerations found at significantly different frequencies in one or more populations. CONCLUSIONS: This study describes allele frequencies observed in African populations at significantly different frequencies relative to at least one other reference population and identifies a subset of variants of clinical interest. Despite the inclusion of mixed sequence coverage datasets, the variants identified pose notable avenues for future inquiries. A subset of variants of clinical interest with statistically significant inter-population frequency differences was identified for further inspection, which provides evidence of an African population-specific variant frequency profile. This study highlights the need for additional research and African genetics data given the presence of this unique frequency profile to better facilitate the genetic pre-screening of patients as a standard of practice in HIV care, particularly on the African continent where HIV is highly prevalent.

Evaluation of the Rho-kinase gene expression and polymorphisms in adult patients with acute appendicitis: a differential impact of gender

SUMMARY OBJECTIVE: Acute appendicitis represents one of the most common causes of acute intra-abdominal emergencies worldwide. In this case-control study, we aimed to investigate associations of Rho-kinase gene expression and polymorphisms with acute appendicitis in a Turkish population. We also aimed to study the effects of gender on these parameters. METHODS: A total of 93 unrelated patients with acute appendicitis and 93 healthy controls in the Department of Emergency Medicine, Erciyes University, between June 2019 and June 2021 were included in this study. Genomic DNA was isolated from peripheral leukocytes, and the LightCycler 480 II real-time polymerase chain reaction was utilized to detect Rho-kinase1 gene rs35996865 and Rho-kinase2 gene rs2230774 (Thr431Asn) polymorphisms. Quantitative real-time polymerase chain reaction was applied to determine Rho-kinase1 and Rho-kinase2 gene expressions. RESULTS: There was a marked increase in Rho-kinase1, but not in Rho-kinase2, mRNA expression, and this increase was evident only in male patients (p=0.0008). No significant differences were found in allele and genotype frequencies for Rho-kinase1 gene rs35996865 and Rho-kinase2 gene rs2230774 polymorphisms between the patients with acute appendicitis and the control group. CONCLUSIONS: Our data imply that Rho-kinase1 (rs35996865) and Rho-kinase2 (rs2230774) gene variants are not risk factors for the development of acute appendicitis in the Turkish population. However, increased mRNA expression of the Rho-kinase1 gene in males indicated that Rho-kinase1 is involved in the pathogenesis of acute appendicitis in a gender-specific way.

Fetal pharmacogenomics: A promising addition to complex neonatal care.

OBJECTIVE: Pharmacogenomics (PGx) characterizes genetic variation in medication response. 85-95% of the population carries actionable PGx variants. No prior studies have demonstrated the application and feasibility of PGx in prenatal testing. We assessed parental desire for PGx findings from fetal exome sequencing (ES), evaluated PGx variants, and reviewed implications for medically complex neonates. METHODS: A prospective cohort undergoing ES for nonimmune hydrops fetalis were offered PGx results as a secondary finding. Seven pharmacogenes with Level A evidence, defined by Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, were tested and reported to patients and referring providers. Medication administration records were reviewed. RESULTS: Most participants (36/40, 90%) desired PGx testing. 32/36 (89%) had potentially actionable PGx diplotypes in six genes: CYP2C19 (20/36, 56%), CYP2C9 (16/36, 44%), CYP2D6 (10/36, 28%), SLCO1B1 (13/36, 36%), TPMT (6/36, 17%), UGT1A1 (4/36, 11%). 12/13 (92%) live births had PGx variants. Neonatal chart review indicated that three medications with CPIC Level A evidence were administered to four neonates. None of the patients received a medication that aligned with an actionable pharmacogenetic variant as defined by Level A CPIC guidance. CONCLUSION: Most participants opted to receive PGx results. 89% had actionable variants, consistent with population estimates. Obtaining fetal PGx data is feasible for medically complex neonates. Further studies are needed for broad clinical application of PGx in fetuses with major congenital abnormalities. Our study demonstrates the potential of PGx as useful preemptive clinical information that could be obtained at the time of fetal exome sequencing for other indications. CLINICALTRIALS: gov Registration: NCT03911531.

The Role of Pharmacogenomics in Opioid Prescribing.

OPINION STATEMENT: Pharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person's genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. Research is accelerating with other opioids, where oxycodone (CYP2D6) and methadone (CYP2B6, ABCB1) already have moderate evidence of an association in terms of drug metabolism and downstream analgesic response and side effects. OPRM1 and COMT are receiving increasing attention and have implications for all opioids, with changes in opioid dosage requirements observed but they have not yet been studied widely enough to be considered clinically actionable. Current evidence indicates that incorporation of pharmacogenomic testing into opioid prescribing practice should focus on the CYP2D6 gene and its actionable variants. Although opioid pharmacogenomic tests are not widely used in clinical practice, the progressively reducing costs and rapid turnover means greater accessibility and affordability to patients, and thus, clinicians will be increasingly asked to provide guidance in this area. The upsurge in pharmacogenomic research will likely discover more actionable gene variants to expand international guidelines to impact opioid prescribing. This rapidly expanding area requires consideration and monitoring by clinicians in order for key findings with clinical implications to be accessible, meaningfully interpretable and communicated.

A novel machine learning-based approach for the computational functional assessment of pharmacogenomic variants.

BACKGROUND: The field of pharmacogenomics focuses on the way a person's genome affects his or her response to a certain dose of a specified medication. The main aim is to utilize this information to guide and personalize the treatment in a way that maximizes the clinical benefits and minimizes the risks for the patients, thus fulfilling the promises of personalized medicine. Technological advances in genome sequencing, combined with the development of improved computational methods for the efficient analysis of the huge amount of generated data, have allowed the fast and inexpensive sequencing of a patient's genome, hence rendering its incorporation into clinical routine practice a realistic possibility. METHODS: This study exploited thoroughly characterized in functional level SNVs within genes involved in drug metabolism and transport, to train a classifier that would categorize novel variants according to their expected effect on protein functionality. This categorization is based on the available in silico prediction and/or conservation scores, which are selected with the use of recursive feature elimination process. Toward this end, information regarding 190 pharmacovariants was leveraged, alongside with 4 machine learning algorithms, namely AdaBoost, XGBoost, multinomial logistic regression, and random forest, of which the performance was assessed through 5-fold cross validation. RESULTS: All models achieved similar performance toward making informed conclusions, with RF model achieving the highest accuracy (85%, 95% CI: 0.79, 0.90), as well as improved overall performance (precision 85%, sensitivity 84%, specificity 94%) and being used for subsequent analyses. When applied on real world WGS data, the selected RF model identified 2 missense variants, expected to lead to decreased function proteins and 1 to increased. As expected, a greater number of variants were highlighted when the approach was used on NGS data derived from targeted resequencing of coding regions. Specifically, 71 variants (out of 156 with sufficient annotation information) were classified as to "Decreased function," 41 variants as "No" function proteins, and 1 variant in "Increased function." CONCLUSION: Overall, the proposed RF-based classification model holds promise to lead to an extremely useful variant prioritization and act as a scoring tool with interesting clinical applications in the fields of pharmacogenomics and personalized medicine.

Follow-Up of Adefovir Dipivoxil Induced Osteomalacia: Clinical Characteristics and Genetic Predictors.

Adefovir dipivoxil (ADV) is widely used for chronic hepatitis B therapy in China. To explore the clinical features and prognosis of ADV-induced osteomalacia and to analyze the association between osteomalacia and genetic variants in 51 drug transporters genes. Clinical and follow-up data of the ADV-treated patients were collected. Target capture sequencing was used to identify genetic variations of 51 drug transporter genes. A total of 193 hepatitis B patients treated with ADV were enrolled, of whom 140 had osteomalacia. The other 53 without osteomalacia were included in the control group. The median duration of ADV treatment before the onset of osteomalacia was 6.5 years (range:1.5-7 years). We found that most patients with osteomalacia had hypophosphatemia, high serum alkaline phosphatase levels, hypouricemia, nondiabetic glycosuria, proteinuria. Stopping ADV administration, supplementing calcitriol and calcium were effective treatments. During 3-6 months of follow-up, the clinical symptoms and biochemical indicators of patients with osteomalacia have been significantly improved. There was no significant difference in duration of adefovir treatment in patients with or without osteomalacia (p = 0.791). Through regression analysis, we found that age was a risk factor for osteomalacia [per 1 year, odds ratio (OR), 1.053; 95% confidence interval (95% CI), 1.020-1.087; p = 0.015]. 1992 single nucleotide variants were found using target capture sequencing. However, the associations of genetic variants of 51 drug transporter genes and the risk of osteomalacia were negligible. Osteomalacia is prone to occur in patients with chronic hepatitis B treated with long-term ADV at a therapeutic dose. After standard treatment, the prognosis is mostly good. We failed to find genetic variants that can predict the risk of ADV-induced osteomalacia.

Genetic Predictors for Sinusoidal Obstruction Syndrome-A Systematic Review.

Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication after hematopoietic stem cell transplantation (HSCT) or antineoplastic treatment without HSCT. Genetic variants were investigated for their association with SOS, but the evidence is inconclusive. We performed a systematic literature review to identify genes, gene variants, and methods of association analyses of genetic markers with SOS. We identified 23 studies after HSCT and 4 studies after antineoplastic treatment without HSCT. One study (4%) performed whole-exome sequencing (WES) and replicated the analysis in an independent cohort, 26 used a candidate-gene approach. Three studies included >200 participants (11%), and six were of high quality (22%). Variants in 34 genes were tested in candidate gene studies after HSCT. Variants in GSTA1 were associated with SOS in three studies, MTHFR in two, and CPS1, CTH, CYP2B6, GSTM1, GSTP1, HFE, and HPSE in one study each. UGT2B10 and LNPK variants were identified in a WES analysis. After exposure to antineoplastic agents without HSCT, variants in six genes were tested and only GSTM1 was associated with SOS. There was a substantial heterogeneity of populations within and between studies. Future research should be based on sufficiently large homogenous samples, adjust for covariates, and replicate findings in independent cohorts.

Micronuclei Formation upon Radioiodine Therapy for Well-Differentiated Thyroid Cancer: The Influence of DNA Repair Genes Variants.

Radioiodine therapy with 131I remains the mainstay of standard treatment for well-differentiated thyroid cancer (DTC). Prognosis is good but concern exists that 131I-emitted ionizing radiation may induce double-strand breaks in extra-thyroidal tissues, increasing the risk of secondary malignancies. We, therefore, sought to evaluate the induction and 2-year persistence of micronuclei (MN) in lymphocytes from 26 131I-treated DTC patients and the potential impact of nine homologous recombination (HR), non-homologous end-joining (NHEJ), and mismatch repair (MMR) polymorphisms on MN levels. MN frequency was determined by the cytokinesis-blocked micronucleus assay while genotyping was performed through pre-designed TaqMan® Assays or conventional PCR-restriction fragment length polymorphism (RFLP). MN levels increased significantly one month after therapy and remained persistently higher than baseline for 2 years. A marked reduction in lymphocyte proliferation capacity was also apparent 2 years after therapy. MLH1 rs1799977 was associated with MN frequency (absolute or net variation) one month after therapy, in two independent groups. Significant associations were also observed for MSH3 rs26279, MSH4 rs5745325, NBN rs1805794, and tumor histotype. Overall, our results suggest that 131I therapy may pose a long-term challenge to cells other than thyrocytes and that the individual genetic profile may influence 131I sensitivity, hence its risk-benefit ratio. Further studies are warranted to confirm the potential utility of these single nucleotide polymorphisms (SNPs) as radiogenomic biomarkers in the personalization of radioiodine therapy.

Farmacogenómica de los anticoagulantes orales: la importancia de establecer algoritmos de dosificación en población chilena

There is an important interindividual variability in dose requirement for coumarinic anticoagulants, which could be explained by genetic and non-genetic factors. Among hereditary factors, there are gene polymorphisms that code the therapeutic target and the main enzyme responsible for their metabolism. However, there are other candidate genes that could modulate dose requirements. The is a paucity of pharmacogenomic platforms to determine dose requirements of coumarinics in the Chilean population. Therefore, algorithms considering different variables to adjust individual dosages are required. Herein, we analyze the available evidence about factors that can modify the effects of vitamin K antagonists and that should be incorporated to dosing algorithms.

Linking Exome Sequencing Data with Drug Response Aberrations.

Next-generation sequencing has prompted the development of numerous -omics applications. Along with experimental procedures, various computational pipelines became available to address the inherent complexities concerning the volume and quality of data. These pipelines are effective and routinely applied; however, interpreting their outcomes into actionable evidence is still poorly addressed. In this context, this work proposes a method for translating patient genomic profiles to drug response aberrations by integrating pharmacogenomic data into sequencing data analysis pipelines.

Utilidad del gen SLCO1B1 como marcador de interés en la farmacogenómica de las estatinas / SLCO1B1 gene utility as a marker of interest in the pharmacogenomics of statins

Resumen Las enfermedades cardiovasculares son la principal causa de muerte en el mundo. Fármacos hipolipemiantes como las estatinas son la primera alternativa en la prevención primaria de eventos cardiovasculares, ictus cerebrales y procedimientos de revascularización. Estos fármacos son inhibidores de la enzima HMG-CoA reductasa, la cual regula la velocidad de la síntesis del colesterol y además aumenta la captación hepática del mismo por la vía del receptor de las LDL. El polipéptido transportador de aniones orgánicos 1B1 (OATP1B1) codificado por el gen SLCO1B1 es uno de los transportadores de captación y eflujo hepático de las estatinas. Por medio de estudios de asociación de genomas completos se han reportado diferentes SNPs dentro del gen SLCO1B1 con capacidad de reducir la captación de estatinas mediada por OATP1B1, por lo que las variaciones en la secuencia de este gen influyen en la farmacocinética y farmacodinámica de estos medicamentos, llegando a causar una condición conocida como miopatía inducida por estatinas. En la actualidad, genes que afectan las terapias cardiovasculares, así como los avances actuales en el campo de las pruebas diagnósticas basadas en la secuenciación de los mismos, ofrecen la posibilidad de revolucionar el diagnóstico y el tratamiento con el fin de validar el riesgo de predicción, pronóstico, prevención y manejo de pacientes con riesgo de enfermedades cardiovasculares, lo cual conducirá al desarrollo de nuevas formas de tratamientos médicos.

Abstract Cardiovascular diseases are the main cause of death in the world. Lipid-lowering drugs like statins are the first alternative in the primary prevention of cardiovascular events, strokes, and revascularisation procedures. These drugs are HMG-CoA reductase inhibitors, which regulate the rate of cholesterol synthesis, as well as increase its liver uptake via the LDL receptor pathway. The organic anion transporter polypeptide 1B1 (OATP1B1) coded by the solute carrier organic anion transporter 1B1 (SLCO1B1) gene is one of the hepatic influx and efflux transporters of statins. In genome-wide association studies (GWAS) different single nucleotide polymorphisms (SNPs) have been reported within the SLCO1B1 gene that are able to reduce the statin uptake mediated by OATP1B1. This suggests that the variations in the sequencing of this gene have an influence on the pharmacokinetics and pharmacodynamics of these drugs, leading to a condition known as statin-induced myopathy. Genes that affect cardiovascular treatments, as well as the current advances in diagnostic tests based on their sequencing, now offer the possibility of revolutionising their diagnosis and treatment. They could be used with the aim of validating risk prediction, prognosis, prevention, and management of patients with a risk of cardiovascular diseases, and will lead to the development of new forms of medical treatments.

Thiopurine intolerance-causing mutations in NUDT15 induce temperature-dependent destabilization of the catalytic site.

Germline mutations in NUDT15 cause thiopurine intolerance during treatment of leukemia or autoimmune diseases. Previously, it has been shown that the mutations affect the enzymatic activity of the NUDT15 hydrolase due to decreased protein stability in vivo. Here we provide structural insights into protein destabilization in R139C and V18I mutants using thermolysin-based proteolysis and H/D exchange followed by mass spectrometry. Both mutants exhibited destabilization of the catalytic site, which was more pronounced at higher temperature. This structural perturbation is shared by the mutations despite their different positions within the protein structure. Reaction products of NUDT15 reverted these conformational abnormalities, demonstrating the importance of ligands for stabilization of a native state of the mutants. This study shows the action of pharmacogenetic variants in NUDT15 in a context of protein structure, which might open novel directions in personalized chemotherapy.