Genetic polymorphisms in ADRB1, ADRB2 and CYP2D6 genes and response to beta-blockers in patients with acute coronary syndrome.

Betablockers (BBs) are prescribed for ischaemia in patients with acute coronary syndrome (ACS). In Spain, bisoprolol and carvedilol are the most prescribed BBs, but patients often had to discontinue them due to adverse effects. Single nucleotide polymorphisms (SNPs) in ADRB1, ADRB2 and CYP2D6 genes have strong evidence of pharmacogenetic association with BBs in heart failure or hypertension, but the evidence in ACS is limited. Therefore, our study focuses on investigating how these genes influence the response to BBs in ACS patients. We analysed the association between SNPs in ADRB1 Gly389Arg (rs1801253) and Ser49Gly (rs1801252), ADRB2 Gly16Arg (rs1042713) and Glu27Gln (rs1042714), and CYP2D* 6 (*2- rs1080985, *4- rs3892097, *10 - rs1065852) and the occurrence of bradycardia/hypotension events during one year of follow-up. We performed an observational study and included 285 ACS-PCI-stent patients. A first analysis including patients treated with bisoprolol and a second analysis including patients treated with other BBs were performed. We found that the presence of the G allele (Glu) of the ADRB2 gene (rs1042714; Glu27Gln) conferred a protective effect against hypotension-induced by BBs; OR (CI 95%) = 0,14 (0,03-0,60), p < 0.01. The ADRB2 (rs1042713; Gly16Arg) GG genotype could also prevent hypotensive events; OR (CI 95%) = 0.49 (0.28-0.88), p = 0015. SNPs in ADRB1 and CYP2D6 * 2, CYP2D6 * 4 weren´t associated with primary events. The effect of CYP2D6 * 10 does not seem to be relevant for the response to BBs. According to our findings, SNPs in ADRB2 (rs1042713, rs1042714) could potentially affect the response and tolerance to BBs in ACS-patients. Further studies are necessary to clarify the impact of ADRB2 polymorphisms.

Genetic Polymorphisms in VEGFR Coding Genes (FLT1/KDR) on Ranibizumab Response in High Myopia and Choroidal Neovascularization Patients.

A severe form of myopia defined as pathologic/high myopia is the main cause of visual impairment and one of the most frequent causes of blindness worldwide. It is characterized by at least 6 diopters or axial length (AL) of eyeball > 26 mm and choroidal neovascularization (CNV) in 5 to 10% of cases. Ranibizumab is a humanized recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A (VEGF-A) used in the treatment of CNV. It acts by preventing VEGF-A from interacting with its receptors (VEGFR-1 and -2) encoded by the FLT1 and KDR genes. Several studies found that the KDR and FLT1 genotypes may represent predictive determinants of efficacy in ranibizumab-treated neovascular age-related macular degeneration (nAMD) patients. We performed a retrospective study to evaluate the association of single nucleotide polymorphisms (SNPs) in VEGFR coding genes with the response rate to ranibizumab in patients with high myopia and CNV. In the association study of genotypes in FLT1 with the response to ranibizumab, we found a significant association between two FLT1 variants (rs9582036, rs7993418) with ranibizumab efficacy at the 12-month follow-up. About the KDR gene, we found that two KDR variants (rs2305948, rs2071559) are associated with best-corrected visual acuity (BCVA) improvement and KDR (rs2239702) is associated with lower rates of BCVA worsening considering a 12-month follow-up period.

Pharmacogenomics decision support in the U-PGx project: Results and advice from clinical implementation across seven European countries.

BACKGROUND: The clinical implementation of pharmacogenomics (PGx) could be one of the first milestones towards realizing personalized medicine in routine care. However, its widespread adoption requires the availability of suitable clinical decision support (CDS) systems, which is often impeded by the fragmentation or absence of adequate health IT infrastructures. We report results of CDS implementation in the large-scale European research project Ubiquitous Pharmacogenomics (U-PGx), in which PGx CDS was rolled out and evaluated across more than 15 clinical sites in the Netherlands, Spain, Slovenia, Italy, Greece, United Kingdom and Austria, covering a wide variety of healthcare settings. METHODS: We evaluated the CDS implementation process through qualitative and quantitative process indicators. Quantitative indicators included statistics on generated PGx reports, median time from sampled upload until report delivery and statistics on report retrievals via the mobile-based CDS tool. Adoption of different CDS tools, uptake and usability were further investigated through a user survey among healthcare providers. Results of a risk assessment conducted prior to the implementation process were retrospectively analyzed and compared to actual encountered difficulties and their impact. RESULTS: As of March 2021, personalized PGx reports were produced from 6884 genotyped samples with a median delivery time of twenty minutes. Out of 131 invited healthcare providers, 65 completed the questionnaire (response rate: 49.6%). Overall satisfaction rates with the different CDS tools varied between 63.6% and 85.2% per tool. Delays in implementation were caused by challenges including institutional factors and complexities in the development of required tools and reference data resources, such as genotype-phenotype mappings. CONCLUSIONS: We demonstrated the feasibility of implementing a standardized PGx decision support solution in a multinational, multi-language and multi-center setting. Remaining challenges for future wide-scale roll-out include the harmonization of existing PGx information in guidelines and drug labels, the need for strategies to lower the barrier of PGx CDS adoption for healthcare institutions and providers, and easier compliance with regulatory and legal frameworks.

Genetic Polymorphisms Affecting Ranibizumab Response in High Myopia Patients.

High myopia is an ophthalmic pathology that affects half of the young adults in the United States and Europe and it is predicted that a third of the world's population could be nearsighted at the end of this decade. It is characterized by at least 6 diopters or axial length > 26 mm and, choroidal neovascularization (CNV) in 5 to 11% of cases. Ranibizumab is a recombinant humanized monoclonal antibody fragment. It is an anti-vascular endothelial growth factor (anti-VEGF) drug used in the treatment of CNV. Many genetic polymorphisms have been associated with interindividual differences in the response to ranibizumab, but these associations were not yet assessed among patients with high myopia and CNV. We performed a retrospective study assessing the association of genetic polymorphisms with response to ranibizumab in patients with CNV secondary to high myopia (mCNV). We included genetic polymorphisms previously associated with the response to drugs used in CNV patients (bevacizumab, ranibizumab, aflibercept, and photodynamic therapy (PDT)). We also included genetic variants in the VEGFA gene. Based on our results, ARMS2 (rs10490924) and CFH (rs1061170) are associated with response to ranibizumab in high myopia patients; and, included VEGFA genetic polymorphisms are not associated with ranibizumab response in our population but might be related to a higher risk of CNV.

Pharmacogenetic polymorphisms affecting bisoprolol response.

ß-blockers are commonly prescribed to treat multiple cardiovascular (CV) diseases, but, frequently, adverse drug reactions and intolerance limit their use in clinical practice. Interindividual variability in response to ß-blockers may be explained by genetic differences. In fact, pharmacogenetic interactions for some of these drugs have been widely studied, such as metoprolol. But studies that explore genetic variants affecting bisoprolol response are inconclusive, limited or confusing because of mixed results with other ß-Blockers, different genetic polymorphisms observed, endpoint studied etc. Because of this, we performed a systematic review in order to find relevant genetic variants affecting bisoprolol response. We have found genetic polymorphism in several genes, but most of the studies focused in ADRB variants. The ADRB1 Arg389Gly (rs1801253) was the most studied genetic polymorphism and it seems to influence the response to bisoprolol, although studies are inconclusive. Even, we performed a meta-analysis about its influence on systolic/diastolic blood pressure in patients treated with bisoprolol, but this did not show statistically significant results. In conclusion, many genetic polymorphisms have been assessed about their influence on patients´ response to bisoprolol and the ADRB1 Arg389Gly (rs1801253) seems the most relevant genetic polymorphism in this regard but results have not been confirmed with a meta-analysis. Our results support the need of further studies about the impact of genetic variants on bisoprolol response, considering different genetic polymorphisms and conducting single and multiple SNPs analysis, including other clinical parameters related to bisoprolol response in a multivariate study.

Genetic Variants Affecting Anti-VEGF Drug Response in Polypoidal Choroidal Vasculopathy Patients: A Systematic Review and Meta-Analysis.

Polypoidal choroidal vasculopathy (PCV) is usually regarded as a subtype of choroidal neovascularization (CNV) that is secondary to age-related macular degeneration (AMD) characterized by choroidal vessel branching, ending in polypoidal lesions. Despite their close association, PCV and neovascular AMD have shown differences, especially regarding patients' treatment response. Currently, antivascular endothelial growth factor (anti-VEGF) drugs, such as ranibizumab, bevacizumab and aflibercept, have demonstrated their efficacy in CNV patients. However, in PCV, anti-VEGF treatments have shown inconclusive results. Many genetic polymorphisms have been associated with a variable response in exudative/wet AMD patients. Thus, the aim of this study is to explore the genetic variants affecting anti-VEGF drug response in PCV patients. In this regard, we performed a systematic review and meta-analysis. We found four variants (CFH I62V, CFH Y402H, ARMS2 A69S, and HTRA1-62A/G) that have been significantly related to response. Among them, the ARMS2 A69S variant is assessed in our meta-analysis. In conclusion, in order to implement anti-VEGF pharmacogenetics in clinical routines, further studies should be performed, distinguishing physio-pathogenic circumstances between PCV and exudative AMD and the combined effect on treatment response of different genetic variants.

Generating evidence for precision medicine: considerations made by the Ubiquitous Pharmacogenomics Consortium when designing and operationalizing the PREPARE study.

OBJECTIVES: Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based pharmacogenomics approach to guide pharmacotherapy is lacking. Therefore, the Ubiquitous Pharmacogenomics Consortium initiated the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. Here, we provide an overview of considerations made to mitigate multiple methodological challenges that emerged during the design. METHODS: An evaluation of considerations made when designing the PREPARE study across six domains: study aims and design, primary endpoint definition and collection of adverse drug events, inclusion and exclusion criteria, target population, pharmacogenomics intervention strategy, and statistical analyses. RESULTS: Challenges and respective solutions included: (1) defining and operationalizing a composite primary endpoint enabling measurement of the anticipated effect, by including only severe, causal, and drug genotype-associated adverse drug reactions; (2) avoiding overrepresentation of frequently prescribed drugs within the patient sample while maintaining external validity, by capping drugs of enrolment; (3) designing the pharmacogenomics intervention strategy to be applicable across ethnicities and healthcare settings; and (4) designing a statistical analysis plan to avoid dilution of effect by initially excluding patients without a gene-drug interaction in a gatekeeping analysis. CONCLUSION: Our design considerations will enable quantification of the collective clinical utility of a panel of pharmacogenomics-markers within one trial as a proof-of-concept for pharmacogenomics-guided pharmacotherapy across multiple actionable gene-drug interactions. These considerations may prove useful to other investigators aiming to generate evidence for precision medicine.

Pharmacogenetics in the Treatment of Cardiovascular Diseases and Its Current Progress Regarding Implementation in the Clinical Routine.

There is a special interest in the implementation of pharmacogenetics in clinical practice, although there are some barriers that are preventing this integration. A large part of these pharmacogenetic tests are focused on drugs used in oncology and psychiatry fields and for antiviral drugs. However, the scientific evidence is also high for other drugs used in other medical areas, for example, in cardiology. In this article, we discuss the evidence and guidelines currently available on pharmacogenetics for clopidogrel, warfarin, acenocoumarol, and simvastatin and its implementation in daily clinical practice.

The study protocol for a non-randomized controlled clinical trial using a genotype-guided strategy in a dataset of patients who undergone percutaneous coronary intervention with stent.

This article contains data related to the research article entitled "Results of genotype-guided antiplatelet therapy in patients undergone percutaneous coronary intervention with stent" (J. Sánchez-Ramos, C.L. Dávila-Fajardo, P. Toledo Frías, X. Díaz Villamarín, L.J. Martínez-González, S. Martínez Huertas, F. Burillo Gómez, J. Caballero Borrego, A. Bautista Pavés, M.C. Marín Guzmán, J.A. Ramirez Hernández, C. Correa Vilches, J. Cabeza Barrera, 2016) (1). This data article reports, for the first time, about the non-randomized clinical trial protocol that check if CYP2C19/ABCB1 genotype-guided strategy in which the choice of antiplatelet therapy is based on the genetic test, reduces the rates of cardiovascular events and bleeding compared to a non-tailored strategy in patients undergone percutaneous coronary intervention (PCI) with stent. The data included in this article are: design and setting of the study, study population, inclusion and exclusion criteria, definition of the intervention, objectives, variables (baseline characteristics and during the follow-up), study procedures, collection and treatment of the biological sample, genotyping, withdrawal criteria, sample size, statistic analysis, ethical aspects, information sheet and consent form. The authors confirm that this study has been registered in Eudra CT (Eudra CT: 2016-001294-33).

Results of genotype-guided antiplatelet therapy in patients who undergone percutaneous coronary intervention with stent.

BACKGROUND: Clopidogrel has provided beneficial effects in acute coronary syndrome and percutaneous coronary intervention. Different polymorphisms have been associated with differences in clopidogrel response. The aim of this study was to check if CYP2C19/ABCB1-genotype-guided strategy reduces the rates of cardiovascular events and bleeding. METHODS: This experimental study included patients undergoing percutaneous coronary intervention with stent. The prospective genotype-guided strategy (intervention group) was compared against a retrospective non-tailored strategy (control group). Primary efficacy endpoint was the composite of cardiovascular death, acute coronary syndrome or stroke during 12months after intervention. Secondary endpoint was to compare the efficacy of the different antiplatelet therapies used in genotyping conditions. RESULTS: The study included 719 patients undergone stent, more than 86% with acute coronary syndrome. The primary endpoint occurred in 32 patients (10.1%) in the genotyping group and in 59 patients (14.1%) in the control group (HR 0.63, 95% CI (0.41-0.97), p =0.037). There was no difference in The Thrombolysis in Myocardial Infarction major and minor bleeding criteria between the two groups (4.1% vs. 4.7%, HR=0.80, 95% CI (0.39-1.63), p=0.55). In intervention group, there was no difference in the rate of events in patients treated with clopidogrel versus patients treated with other antiplatelet treatments (9.1% vs 11.5% p=0.44), or bleeding (3.7% vs 4.6%, p=0.69). CONCLUSIONS: The genotype-guided strategy could reduce the rates of composite of cardiovascular events and bleeding during 12months after percutaneous coronary intervention compared to a non-genotype-guide strategy.

Genetic polymorphisms influence on the response to clopidogrel in peripheral artery disease patients following percutaneous transluminal angioplasty.

AIM: To study the association of ABCB1 and CYP2C19 polymorphisms and the clopidogrel response in Spanish peripheral artery disease patients following percutaneous transluminal angioplasty (PTA) and to perform a meta-analysis. MATERIALS & METHODS: 72 patients were recruited and 122 patients included in the meta-analysis. We evaluated the effect of ABCB1 3435 C>T, CYP2C19*2 and CYP2C19*3 and primary end point (restenosis/occlusion of the treated lesions) during 12 months after PTA. RESULTS: CYP2C19*2 and/or ABCB1 TT patients were associated with primary end point (OR: 5.00; 95% CI: 1.75-14.27). The meta-analysis confirmed the association of CYP2C19*2 and new atherothrombotic ischemic events (OR: 5.40; 95% CI: 2.30-12.70). CONCLUSION: The CYP2C19 and ABCB1 polymorphisms could be genetic markers of cardiovascular events in peripheral artery disease patients following PTA treated with clopidogrel.

A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population.

There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11-21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases.

FcGR genetic polymorphisms and the response to adalimumab in patients with rheumatoid arthritis.

AIM: The aim of our study was to explore the potential of FcGR genetic polymorphisms as a predictor of adalimumab efficacy in rheumatoid arthritis (RA) patients. MATERIALS & METHODS: The study population was composed of 302 Dutch RA patients receiving adalimumab therapy. The FcGR2A (R131>H; rs1801274) and FcGR3A (F158>V; rs396991) genetic variants were genotyped using the TaqMan(®) allelic discrimination technology. Treatment outcome was evaluated with the use of the 28-joint disease activity score criteria (DAS28) and good response and remission were classified according to European League Against Rheumatism (EULAR) criteria. RESULTS: Comparing allelic frequencies between responders and nonresponders, the presence of the FcGR2A*R allele was associated with EULAR good response at 14 weeks (p = 0.017, odds ratio: 1.53, 95% CI: 1.08-2.17). No significant association was found for FcGR3A, with good response or remission. The combined effect of both FcGR2A and FcGR3A SNPs showed a trend for association with EULAR good response (p-value = 0.041, odds ratio: 1.38, 95% CI: 1.01-1.89). CONCLUSION: Our results indicate that FcGR polymorphisms could be a determinant of adalimumab efficacy in RA patients. Original submitted 28 July 2014; Revision submitted 19 December 2014.

IL2/IL21 region polymorphism influences response to rituximab in systemic lupus erythematosus patients.

To determine whether the IL2/IL21 region, a general autoimmunity locus, contributes to the observed variation in response to rituximab in patients with systemic lupus erythematosus as well as to analyze its influence in a cohort including other autoimmune diseases. rs6822844 G/T polymorphism at the IL2-IL21 region was analyzed by TaqMan assay in 84 systemic lupus erythematosus (SLE) and 60 different systemic autoimmune diseases Spanish patients receiving rituximab. Six months after the first infusion patients were classified, according to the EULAR criteria, as good responders, partial responders and non-responders. A statistically significant difference was observed in GG genotype frequency between responder (total and partial response) (83.56%) and non-responder (45.45%) SLE patients (p=0.010, odds ratio (OR)=6.10 [1.28-29.06]). No association with the response was evident in the group of patients with autoimmune diseases other than lupus. Furthermore, when both groups of patients were pooled in a meta-analysis, a reduced statistical significance of the association was observed (p=0.024, OR=3.53 [1.06-11.64]). Our results show for a first time that IL2-IL21 region seems to play a role in the response to rituximab in SLE patients but not in other autoimmune diseases.

Genetic risk factors for drug-induced liver injury in rheumatoid arthritis patients using low-dose methotrexate.

Low-dose methotrexate (MTX) is part of the mainstay of rheumatoid arthritis treatment. Hepatotoxicity is among the most feared side effects of low-dose MTX and is associated with increased morbidity. At present, histological evaluation of liver biopsies is the gold standard to retrospectively diagnose MTX-induced liver damage. Genetic markers present an interesting opportunity to preemptively identify patients at risk for MTX-induced hepatotoxicity. Here, we will review the literature on candidate genetic markers for the risk of MTX-induced hepatotoxicity. These candidate genetic markers include polymorphisms in the gene encoding the enzyme MTHFR.

Association of the FCGR3A-158F/V gene polymorphism with the response to rituximab treatment in Spanish systemic autoimmune disease patients.

Rituximab is being used as treatment for systemic autoimmune diseases. The objective of this study was to determine whether the genetic variant in the Fc gamma-receptor III a (FCGR3A) gene, 158F/V, contributes to the observed variation in response to rituximab in patients with systemic autoimmune diseases. DNA samples from 132 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for FCGR3A-158F/V (rs396991) gene polymorphism using the TaqMan(®) allelic discrimination technology. Six months after infusion with rituximab we evaluated the response to the drug: 61% of the patients showed a complete response, partial 27% and 12% did not respond to the treatment. A statistically significant difference was observed in V allele frequency between responder (38%) and nonresponder (16%) patients (p=0.01; odds ratio [OR]=3.24, 95% confidence interval [CI] 1.17-11.1). Rituximab was also more effective in V allele carriers (94%) than in homozygous FF patients (81%): p=0.02; OR=3.96, 95% CI 1.10-17.68. These results suggest that FCGR3A-158F/V (rs396991) gene polymorphism play a role in the response to rituximab in autoimmune diseases. Validation of these findings in independent cohorts is warranted.

Association between -174 interleukin-6 gene polymorphism and biological response to rituximab in several systemic autoimmune diseases.

Rituximab has become a pivotal treatment for systemic autoimmune diseases. The aim of this study was to determine whether the genetic variant -174 IL-6 contributes to differences in the response to rituximab in patients with systemic autoimmune diseases, including systemic lupus erythematosus (SLE), inflammatory myopathies, anti-neutrophil cytoplasmic antibody-mediated vasculitis, systemic sclerosis, Sjöegren's syndrome, rheumatoid arthritis, and autoimmune hemolytic anemia. DNA samples from 144 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for -174 IL-6 (rs1800795) gene polymorphism using the TaqMan(®) allelic discrimination technology. Six months after the first infusion with rituximab, we evaluated the response to the drug: 60.4% of the patients showed a complete response, partial 27.8%, and 11.8% did not respond to the treatment. The CC genotype frequency was significantly increased in nonresponders with respect to responders (23.5% vs. 7.1%, respectively; p=0.049; odds ratio (OR)=4.03, 95% confidence intervals (CI) 0.78-16.97). According to the genotype distribution, rituximab was effective in 69.2% of the CC carriers, 91.9% of the CG carriers, and 88.4% of the GG carriers. A similar trend was observed when SLE patients were analyzed separately (27.3% carried CC homozygosis in nonresponders and 6.9% in responders; p=0.066; OR=5.10, 95% CI 0.65-31.73). Rituximab was effective in 62.5% of the CC carriers, 88.9% of the GC carriers, and 90% of the GG carriers. These results suggest that -174 IL-6 (rs1800795) gene polymorphism plays a role in the response to rituximab in systemic autoimmune diseases. Validation of these findings in independent cohorts is warranted.