What is already known on this topic?

• Pharmacogenetics is not a new science; it has deep historical roots dating back to the early 20th century (initial descriptions of pharmacogenetic phenomena, discovery of cytochrome P450).
• It has evolved from studying isolated adverse drug reactions to a systemic understanding of the polygenic nature of the response to most drugs.
• Associations have been established between polymorphisms in specific genes (CYP2C19, CYP2D6, TPMT, DPYD, etc.) and drug efficacy/safety.
• Implementation into clinical practice in the Russian Federation faces significant barriers: insufficient integration into clinical guidelines, economic constraints, regulatory gaps, and a lack of knowledge among physicians.

What does this article add new?

• The article presents a strategic program and vision for the development of pharmacogenetics in Russia for the next decade (until 2035).
• It announces the creation of new large-scale infrastructure projects: a National DNA Biobank, a National Pharmacogenetic Knowledge Base, and a clinical decision support system (CDSS).
• It defines the specific technological trends the discipline will focus on: a shift towards multiomics approaches (genomics, proteomics, metabolomics), active use of artificial intelligence for risk prediction, and reducing the cost of whole-genome sequencing.
• It outlines plans to establish a world-class Center for Predictive Genetics and Pharmacogenetics.

How might this influence clinical practice in the foreseeable future?

• A paradigm shift in prescribing: Moving from the concept of a "standard dose" to personalized prescription based on a genetic passport, sensor data, and AI prediction.
• Increased accessibility: Reduced testing costs will make it a routine procedure not only in major centers but also in primary healthcare.
• Integration into clinical guidelines: The developed algorithms and models will be directly embedded into treatment standards and drug labels.
• Emergence of new services: Creation of drug information centers and the development of telemedicine consultations with clinical pharmacologists for test interpretation.
• Proactive medicine: In oncology, the concept of "pharmacogenomic prophylaxis" for carriers of high-risk mutations may emerge.
• Mandatory testing: In fields like psychiatry, pharmacogenetic testing may become mandatory prior to prescribing therapy.

What is already known on this topic?

Genetics influences antidepressant efficacy. It is known that the response to drugs, particularly Selective Serotonin Reuptake Inhibitors (SSRIs), varies among patients, and some of this variability is due to genetic factors.

Specific genes are being studied. Two key genes of the serotonergic system—SLC6A4 (encodes the serotonin transporter protein) and TPH1 (encodes an enzyme involved in serotonin synthesis)—are targets of pharmacogenetic research.

The results are contradictory. Data on the influence of polymorphisms in these genes (such as rs4795541 in SLC6A4 and rs1800532 in TPH1) on SSRI efficacy are inconsistent and often depend on the patients' ethnicity, the class of antidepressant, and the study design.

What does this study add?

• New data for a specific population. This is the first study conducted on patients with mixed anxiety-depressive disorder from the Republic of Bashkortostan.
• New markers of inefficacy. It was found that in the studied population, the *L/L* genotype of the SLC6A4 gene (rs4795541) and the *A/A* genotype of the TPH1 gene (rs1800532) are associated with lower efficacy of sertraline therapy (evidenced by higher scores on psychometric scales for depression and anxiety throughout the study).
• Confirmation of the hypothesis. The results confirm the hypothesis of a significant influence of these polymorphic variants on the pharmacogenetics of sertraline, but highlight the ethnic specificity of the conclusions.

How might this affect clinical practice in the foreseeable future?

• Potential for personalized medicine. In the future, the results of such studies could form the basis for genetic tests to predict sertraline efficacy before starting treatment.
• Optimizing drug selection. If a patient is found to have the L/L (SLC6A4*) or A/A (TPH1*) genotypes prior to therapy, a physician could consider prescribing a different antidepressant (e.g., from a different pharmacological class) with a higher likelihood of success. This would help reduce the time needed to find an effective therapy and lower the risk of side effects from ineffective treatment.
• Need for further research. For widespread implementation into clinical practice, larger studies on diverse populations across Russia are needed to refine and verify the obtained data, followed by the development of clinical guidelines based on them.

What is already known on this topic?

• Sensitivity to warfarin is individual and highly dependent on genetic polymorphisms, primarily of the CYP2C9 gene (responsible for drug metabolism) and the VKORC1 gene (its target).
• By blocking VKORC1, warfarin inhibits not only the synthesis of clotting factors but also the activation of matrix Gla protein (MGP)—a powerful inhibitor of vascular calcification.
• This links warfarin therapy to the risk of vascular calcification.
• Chronic rheumatic heart disease (CRHD) itself is characterized by progressive calcification of the heart valves.
• The frequency of VKORC1 and CYP2C9 alleles has significant ethnic variations, but data on the Chuvash population were limited.

What does the study add?

• This is the first report of allele frequencies of key pharmacogenetic markers (VKORC1 −1639G>A, CYP2C9*2, CYP2C9*3) specifically in Chuvash patients with CRHD.
• VKORC1 A allele: 48.6%
• T allele (CYP2C9*2): 10.15%
• C allele (CYP2C9*3): 4.05%
• A novel association was established: in this patient cohort, homozygous carriage of the A allele (AA genotype) of the VKORC1 gene was significantly associated with the development of aortic valve calcification (p=0.023).
• The very high prevalence of valve calcification (75.7%) in patients with CRHD was confirmed, with the aortic (50%) and mitral (45.9%) valves most commonly affected.

How might this affect clinical practice in the foreseeable future?

• The obtained data support the feasibility of pharmacogenetic testing in Chuvash patients with CRHD before prescribing warfarin.
• The test results could help personalize anticoagulant therapy. For carriers of the VKORC1 AA genotype, when choosing therapy, a physician would consider not only the increased risk of bleeding due to hypersensitivity to warfarin but also a potentially higher risk of progression of aortic valve calcification.
• This may tip the scales in favor of considering warfarin-alternative anticoagulants (DOACs), if there are no other contraindications (e.g., the presence of a mechanical valve prosthesis), especially in patients with already established calcification.
• For patients who continue warfarin therapy, knowing the genotype will allow for more precise dose titration and enhanced monitoring of the valvular apparatus using echocardiography.

What is already known on this topic?

• Arterial hypertension (AH) is a global problem and a major modifiable risk factor for cardiovascular diseases.
• Genetic variants (polymorphisms) of the CYP2C9 gene (specifically, *2 and *3) significantly affect the metabolism of many drugs by reducing enzyme activity.
• It is known that these polymorphisms affect the pharmacokinetics and efficacy of losartan (another ARB): in carriers of "slow" alleles, its effect is diminished.
• For irbesartan, data were conflicting: some studies showed higher plasma concentrations in carriers of the *3 allele, but this did not always clearly translate into a greater clinical effect.
• Valsartan is considered metabolically independent of the CYP450 system, and no significant influence of CYP2C9 genetics on its efficacy had been previously described.

What does the new study add?

• Direct comparison of two ARBs: This is the first study to directly compare the influence of CYP2C9 polymorphisms on the efficacy of irbesartan and valsartan within a single trial.
• Identification of a short-term effect: The study shows that carrying the *2 and *3 alleles is associated with a more pronounced reduction in blood pressure (both SBP and DBP) after just 3 weeks of therapy with both drugs.
• New data on valsartan: Surprisingly, the study found that the efficacy of valsartan (which is barely metabolized by CYP2C9) is also influenced by these genetic variants, especially in the short term. This is a novel finding that contradicts established views.
• Effect "leveling off" by 3 months: By the end of the 3-month treatment course, no statistically significant difference in efficacy between carriers of different genotypes remained. This suggests that the influence of genetics is most important at the start of treatment.

How might this affect clinical practice in the foreseeable future?

• Rationale for pharmacogenetic testing at therapy initiation: The results indicate the potential benefit of genetic testing (CYP2C9) at the very beginning of AH therapy selection to predict the early treatment response.
• Personalized drug and dose selection: Knowing a patient's genotype could help a physician:
• For irbesartan: In carriers of "slow" alleles, a more powerful initial effect can be expected, potentially allowing for earlier achievement of target BP and less frequent need for therapy intensification (dose increase).
• For valsartan: The discovered association requires further study, but if confirmed, it would also open possibilities for more accurate response prediction.
• Improving treatment adherence: Rapid achievement of target BP levels in the first weeks of treatment can motivate the patient and increase their long-term adherence to therapy.
• Need for further research: For implementation into routine practice, larger-scale studies and an assessment of the cost-effectiveness of this approach are necessary.

What is already known on this topic?

• Falls are a global problem: they are the second leading cause of death from unintentional injuries in the elderly.
• The causes are multifactorial: they include internal (age, diseases) and external (environment) factors, as well as modifiable and non-modifiable ones.
• Medications are a key modifiable risk factor: certain drug classes (psychotropic, cardiovascular, hypoglycemic) significantly increase the risk of falls.
• There is a hypothesis about the role of genetics: it is assumed that individual genetic characteristics (pharmacogenetics), which affect drug metabolism, may indirectly influence the risk of falls, but empirical data is very scarce.

What does this study add?

• A specific study was conducted: this is the first analysis on a Russian cohort (172 patients) of the association between cytochrome P450 gene polymorphisms (*CYP2D6, CYP2C19, CYP3A4/5*) and falls in elderly patients with cardiovascular pathology.
• Main result - no direct link: no statistically significant differences were found in the distribution of the studied genetic variants between the fall group and the control group as a whole.
• But associations were found in subgroups: it was discovered that in patients already taking certain medications (beta-blockers, aspirin, inhaled glucocorticoids, alpha-blockers) and those with comorbid diabetes, carrying heterozygous ("intermediate metabolism") and minor genotypes was associated with an increased risk of falls.
• Conclusion: genetic status by itself does not predict falls, but can be an important modifying risk factor when taking specific medications or having certain diseases.

How might this affect clinical practice in the foreseeable future?

• Risk personalization: in the future, with more data, pharmacogenetic testing could help identify at-risk patients (taking specific medications) who have a higher probability of falls due to their metabolic profile.
• More cautious prescribing: for patients with identified "unfavorable" genotypes, doctors could more carefully adjust doses, avoid polypharmacy, or choose alternative drugs not metabolized by the problematic enzymes.
• Enhanced monitoring: such patients could be placed under closer observation for more active monitoring, education, and fall prevention measures.
• Basis for further research: this work sets the direction for larger and more targeted studies to more accurately determine for which specific "drug-gene" pairs the risk of falls is highest.

What is already known on this topic?

• The combination of CAD and AF requires combined antithrombotic therapy (clopidogrel + anticoagulant) to prevent both thromboembolism and stent thrombosis.
• The main problem with this therapy is the increased risk of hemorrhagic complications, which reduces treatment adherence and worsens the prognosis.
• The efficacy and safety of a key drug (clopidogrel) varies significantly among patients.
• Some of this variability is genetically determined (polymorphism of the CYP2C19 gene), which affects the rate of drug metabolism.
• It was previously shown that carriers of the CYP2C19*17 allele (ultra-rapid metabolizers) may have an increased risk of bleeding.

What does this study add?

• The article provides a visual clinical case of a patient with a high risk of bleeding on standard therapy, for whom genetic testing revealed an "ultra-rapid metabolizer" status (CYP2C19*17/*17).
• In addition to CYP2C19, other polymorphisms (genes ABCB1 and CYP3A5) were found in the patient, which, according to literature, are also associated with an increased risk of bleeding when taking anticoagulants.
• Using a single case, it demonstrates a complex genetic risk profile, not just the influence of a single gene.
• It presents the authors' own research data from 150 patients, confirming that there are statistically significantly more ultra-rapid metabolizers among patients with bleeding (19.2% vs. 3.4%).

How might this affect clinical practice in the foreseeable future?

• It substantiates the feasibility of implementing pharmacogenetic testing (particularly for the CYP2C19*17 polymorphism) into the routine practice of cardiologists for bleeding risk stratification.
• This will allow for therapy personalization at the stage of its prescription: in patients with an identified genetically high risk of bleeding, a shorter course of triple therapy or alternative regimens can be considered immediately.
• Timely therapy adjustment based on genetic data (de-escalation) will help prevent the development of severe bleeding, while maintaining treatment effectiveness and improving patient adherence.
• The "treat the patient, not the disease" approach will become more concrete and technological, which in perspective could reduce the number of hospitalizations and improve patient prognosis.