Clin Pharmacol Ther. 2022 Nov 9. doi: 10.1002/cpt.2790. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) investigates the genetic influence on drug response and is an integral part of precision medicine. While PGx testing is becoming more common in clinical practice and may be reimbursed by Medicare/Medicaid and commercial insurance, interpreting PGx testing results for clinical decision support is still a challenge. The Pharmacogenomics Clinical Annotation Tool (PharmCAT) has been designed to tackle the need for transparent, automatic interpretations of patient genetic data. PharmCAT incorporates a patient's genotypes, annotates PGx information (allele, genotype, and phenotype), and generates a report with PGx guideline recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and/or the Dutch Pharmacogenetics Working Group (DPWG). PharmCAT has introduced new features in the last two years, including a VCF preprocessor, the inclusion of DPWG guidelines, and functionalities for PGx research. For example, researchers can use the VCF preprocessor to prepare biobank-scale data for PharmCAT. In addition, PharmCAT enables the assessment of novel partial and combination alleles that are composed of known PGx variants and can call CYP2D6 genotypes based on SNPs and INDELs in the input VCF file. This tutorial provides materials and detailed step-by-step instructions for how to use PharmCAT in a versatile way that can be tailored to users' individual needs.

PMID:36350094 | DOI:10.1002/cpt.2790

Pharmacogenomics J. 2022 Nov 8. doi: 10.1038/s41397-022-00296-2. Online ahead of print.

ABSTRACT

Head and neck squamous cell carcinomas (HNSCCs) are introduced as the sixth most common cancer in the world. Detection of predictive biomarkers improve early diagnosis and prognosis. Recent cancer researches provide a new avenue for organoids, known as "mini-organs" in a dish, such as patient-derived organoids (PDOs), for cancer modeling. HNSCC burden, heterogeneity, mutations, and organoid give opportunities for the evaluation of drug sensitivity/resistance response according to the unique genetic profile signature. The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) nucleases, as an efficient genome engineering technology, can be used for genetic manipulation in three-dimensional (3D) organoids for cancer modeling by targeting oncogenes/tumor suppressor genes. Moreover, single-cell analysis of circulating tumor cells (CTCs) improved understanding of molecular angiogenesis, distance metastasis, and drug screening without the need for tissue biopsy. Organoids allow us to investigate the biopathogenesis of cancer, tumor cell behavior, and drug screening in a living biobank according to the specific genetic profile of patients.

PMID:36347937 | DOI:10.1038/s41397-022-00296-2

Epilepsy Behav Rep. 2022 Oct 19;20:100568. doi: 10.1016/j.ebr.2022.100568. eCollection 2022.

ABSTRACT

Pediatric acute liver failure (PALF) is a rare and life-threatening clinical syndrome for which drug-induced liver injury is a cause. Lamotrigine (LTG) is generally a safe and effective antiseizure medication, and PALF related to LTG has rarely been reported. Here, we describe two cases of PALF associated with LTG in children with epilepsy. In both patients, LTG was used in combination with valproic acid at an initial dose exceeding the recommended dose, which increased the risk of adverse reactions. In addition, single nucleotide polymorphisms of genes associated with the pharmacokinetics and pharmacodynamics of LTG were selected for pharmacogenomic testing. However, the results revealed that genotypes of the patients had variable effects on the serum concentration and therapeutic responsiveness of LTG and therefore did not explain the clinical manifestations well. The findings of this case report caution clinicians to be aware of the risk of liver failure when using antiseizure medication in polytherapy, especially LTG in combination with valproic acid. When administered to children, the recommended dosage of LTG should be strictly followed. Further pharmacogenomic studies are needed to help improve the efficacy and safety of epilepsy treatment in the future.

PMID:36345310 | PMC:PMC9636542 | DOI:10.1016/j.ebr.2022.100568

Pediatr Neonatol. 2022 Oct 25:S1875-9572(22)00224-8. doi: 10.1016/j.pedneo.2022.07.012. Online ahead of print.

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the global coronavirus disease 2019 (COVID-19) pandemic. Rapid identification and isolation of patients infected with SARS-CoV-2 are critical methods for blocking COVID-19 transmission. The advantages of antigen tests, such as their relatively low cost and short turnaround time, can contribute to the prompt identification of infectious individuals. However, the diagnostic accuracy of antigen tests for COVID-19 in children remains inconclusive. This meta-analysis aimed to evaluate the diagnostic performance of antigen tests for SARS-CoV-2 in the pediatric population.

METHODS: We conducted a literature search for relevant studies in the PubMed, Embase, Google Scholar, and Biomed Central databases. Studies evaluating the diagnostic accuracy of antigen tests for SARS-CoV-2 in pediatric patients were included. In addition, we included studies that provided sufficient data to construct a 2 × 2 table on a per-patient basis. The final literature search was performed on October 10, 2021. Days after symptom onset, asymptomatic and symptomatic individuals may have been potential sources of heterogeneity. The overall sensitivity and specificity of the antigen tests were generated using a bivariate random-effects model.

RESULTS: Five studies with 4400 participants were included. The meta-analysis of antigen tests generated a pooled sensitivity of 65.9% (95% CI: 52.8%-77.0%) and pooled specificity of 99.9% (95% CI: 98.9%-100.0%). A subgroup analysis of studies reporting antigen test data for symptomatic patients showed a pooled sensitivity of 64.5% and a pooled specificity of 99.7%. The subgroup analysis of studies that included 881 asymptomatic participants generated a pooled sensitivity of 48.4% and a pooled specificity of 99.5%.

CONCLUSION: Antigen tests exhibit moderate sensitivity and high specificity for detecting SARS-CoV-2 in children. Antigen tests might have moderate sensitivity for detecting SARS-CoV-2 in symptomatic children, and serial testing might effectively prevent further SARS-CoV-2 transmission.

PMID:36344413 | DOI:10.1016/j.pedneo.2022.07.012

Cancer Lett. 2022 Nov 4:215994. doi: 10.1016/j.canlet.2022.215994. Online ahead of print.

ABSTRACT

The androgen inactivating UGT2B28 pathway emerges as a predictor of progression in prostate cancer (PCa). However, the clinical significance of UGT2B28 tumoral expression and its contribution to PCa progression remain unclear. Using the Canadian Prostate Cancer Biomarker Network biobank (CPCBN; n = 1512), we analyzed UGT2B28 tumor expression in relation to clinical outcomes in men with localized PCa. UGT2B28 was overexpressed in tumors compared to paired normal adjacent prostatic tissue and was associated with inferior outcomes. Functional analyses indicated that UGT2B28 promoted cell proliferation, and its expression was regulated by the androgen receptor (AR)/ARv7. Mechanistically, UGT2B28 was shown to be a protein partner of the endocytic adaptor protein huntingtin-interacting protein 1 (HIP1), increasing its stability and priming AR/epidermal growth factor receptor (EGFR) pathways, leading to ERK1/2 activation triggering cell proliferation and epithelial-to-mesenchymal transition (EMT). HIP1 knockdown in UGT2B28 positive cells, and dual pharmacological targeting of AR and EGFR pathways, abolished cell proliferative advantages conferred by UGT2B28. In conclusion, UGT2B28 is a prognosticator of progression in localized PCa, regulates both AR and EGFR oncogenic signaling pathways via HIP1, and therefore can be therapeutically targeted by using combination of existing AR/EGFR inhibitors.

PMID:36343786 | DOI:10.1016/j.canlet.2022.215994

J Cardiovasc Aging. 2022 Oct;2(4):45. doi: 10.20517/jca.2022.36. Epub 2022 Sep 13.

NO ABSTRACT

PMID:36340925 | PMC:PMC9624469 | DOI:10.20517/jca.2022.36

Front Pharmacol. 2022 Oct 19;13:1040591. doi: 10.3389/fphar.2022.1040591. eCollection 2022.

ABSTRACT

Chaihu-Shugan-San (CSS) is a traditional botanical drug formula often prescribed to treat depression in oriental countries, but its pharmacotherapeutic mechanism remains unknown. It was recently reported that CSS alters the composition of intestinal microflora and related metabolites such as bile acids (BAs). Since the intestinal microflora affects physiological functions of the brain through the gut-microbiota-brain axis, herein we investigated whether CSS altered BA levels, gut microflora, and depression-like symptoms in chronic unpredictable mild stress (CUMS) mice, a well-established mouse model of depression. Furthermore, we determined whether BA manipulation and fecal microbiota transplantation altered CSS antidepressant actions. We found that the BA chelator cholestyramine impaired the antidepressant effects of CSS, which was partially rescued by dietary cholic acid. CSS increased the relative abundance of Parabacteroides distasonis in the colon of CUMS mice, and increased serum levels of various BAs including hyocholic acid (HCA) and 7-ketodeoxycholic acid (7-ketoDCA). Furthermore, gut bacteria transplantation from CSS-treated mice into untreated or cholestyramine-treated CUMS mice restored serum levels of HCA and 7-ketoDCA, alleviating depression-like symptoms. In the hippocampus, CSS-treated mice had decreased expression of genes associated with BA transport (Bsep and Fxr) and increased expression of brain-derived neurotrophic factor and its receptor, TrkB. Overall, CSS increases intestinal P. distasonis abundance, leading to elevated levels of secondary BAs in the circulation and altered expression of hippocampal genes implicated in BA transport and neurotrophic signaling. Our data strongly suggest that the gut microbiota-brain axis contributes to the potent antidepressant action of CSS by modulating BA metabolism.

PMID:36339629 | PMC:PMC9627339 | DOI:10.3389/fphar.2022.1040591

Psychopharmacol Bull. 2022 Oct 27;52(4):52-60.

ABSTRACT

BACKGROUND: CYP2D6 subfamily isoenzymes play an important role in the biotransformation of haloperidol, and their activity may influence the efficacy and safety of haloperidol. The use of haloperidol is often associated with the occurrence of adverse drug reactions (ADRs), such as dyskinesia, acute dystonia, and orthostatic hypotension. Previous studies have demonstrated the relationship between the CYP2D6*4 genetic polymorphism and CYP2D6 activity, as well as haloperidol efficacy and safety rates.

PURPOSE: To evaluate the association of CYP2D6*4 genetic polymorphism with the steady-state concentration of haloperidol in patients with acute alcohol-induced psychotic disorders (AIPDs).

MATERIAL AND METHODS: The study involved 100 male patients with AIPD (average age 41.4 ± 14.4 years) who received haloperidol by injections in a dose of 5-10 mg/day. The efficacy profile was assessed using a validated psychometric PANSS scale (Positive and Negative Syndrome Scale). Therapy safety was assessed using the internationally validated UKU (Side-Effect Rating Scale) and SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scales. Genotyping was performed with the real-time polymerase chain reaction.

RESULTS: We revealed the statistically significant results in terms of therapy safety evaluation (dynamics of the UKU scores: (GG) 8.00 [7.00; 10.00], (GA) 15.0 [9.25; 18.0], p < 0.001; dynamics of the SAS scores: (GG) 11.0 [9.0; 14.0], (GA) 14.50 [12.0; 18.0], p < 0.001. Pharmacokinetic study showed a statistically significant difference across the groups with different genotypes: (GG) 3.13 [2.32; 3.95], (GA) 3.89 [2.92; 5.26], p = 0.010.

CONCLUSION: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients who carry the GG genotype. It was shown that CYP2D6*4 genetic polymorphism has a statistically significant effect on the steady-state concentration of haloperidol.

PMID:36339274 | PMC:PMC9611797

Neuroophthalmology. 2022 Aug 2;46(5):304-313. doi: 10.1080/01658107.2022.2100916. eCollection 2022.

ABSTRACT

Tuberculosis (TB) is a global health problem with the major brunt of disease occurring in developing countries. The cornerstone of treatment of TB is anti-tubercular therapy (ATT), which includes rifampicin, isoniazid, pyrazinamide and ethambutol. Because of emerging drug resistance, treatment failures, defaulters and increasing incidence of disseminated and extrapulmonary TB, the guidelines have been modified in some countries. Ethambutol is prescribed for longer times (in some cases >8 months) and hence the incidence of ethambutol-induced optic neuropathy (EtON) is expected to rise. The fundamental question which needs explanation is why only a small subset of patients on ethambutol are prone to develop loss of vision. This review focuses on available genetic studies which provide evidence that mitochondria are the likely substrates involved in the final pathway of reactive oxidative damage of the papillo-macular bundle. Genetic analysis of mitochondrial mutations encoding genes involved in oxidative phosphorylation pathways may help in isolating the subset of patients who are genetically susceptible. If the groups having high risk of developing EtON are recognised then prolonged duration of ethambutol treatment can be avoided in these susceptible individuals. A better understanding of the pathophysiology will also pave the way for the development of management strategies in this condition.

PMID:36337233 | PMC:PMC9635551 | DOI:10.1080/01658107.2022.2100916

Int J Infect Dis. 2022 Nov 3:S1201-9712(22)00582-3. doi: 10.1016/j.ijid.2022.10.044. Online ahead of print.

ABSTRACT

OBJECTIVE: This study reported severe respiratory syndrome coronavirus-2 (SARS-CoV-2) whole genome sequencing results from June 2021 to January 2022 from seven genome sequencing centers in Malaysia as part of the national surveillance program.

METHODS: Coronavirus disease 2019 (COVID-19) samples that tested positive by reverse transcription polymerase chain reaction and with CT values <30 were obtained throughout Malaysia. Sequencing of SARS-CoV-2 complete genomes was performed using Illumina, Oxford Nanopore, or Ion Torrent platforms. A total of 6163 SARS-CoV-2 complete genome sequences were generated over the surveillance period. All sequences were submitted to the Global Initiative on Sharing All Influenza Data (GISAID) database.

RESULTS: From June 2021 to January 2022, Malaysia experienced the fourth wave of COVID-19 dominated by the Delta variant of concern (VOC) including the original B.1.617.2 lineage and descendant AY lineages. The B.1.617.2 lineage was identified as the early dominant circulating strain throughout the country but over time was displaced by AY.59 and AY.79 lineages in Peninsular (West) Malaysia, and the AY.23 lineage in East Malaysia. In December 2021, pilgrims returning from Saudi Arabia facilitated the introduction and spread of the BA.1 lineage (Omicron VOC) in the country.

CONCLUSION: The changing trends of circulating SARS-CoV-2 lineages were identified, with differences observed between West and East Malaysia. This initiative highlighted the importance of leveraging research expertise in the country to facilitate pandemic response and preparedness.

PMID:36336246 | DOI:10.1016/j.ijid.2022.10.044

Nat Commun. 2022 Nov 5;13(1):6694. doi: 10.1038/s41467-022-34116-9.

ABSTRACT

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population.

PMID:36335097 | DOI:10.1038/s41467-022-34116-9

Malar J. 2022 Nov 4;21(1):314. doi: 10.1186/s12936-022-04340-1.

ABSTRACT

The global burden of malaria continues to be a significant public health concern. Despite advances made in therapeutics for malaria, there continues to be high morbidity and mortality associated with this infectious disease. Sub-Saharan Africa continues to be the most affected by the disease, but unfortunately the region is burdened with indigent health systems. With the recent increase in lifestyle diseases, the region is currently in a health transition, complicating the situation by posing a double challenge to the already ailing health sector. In answer to the continuous challenge of malaria, the African Union has started a "zero malaria starts with me" campaign that seeks to personalize malaria prevention and bring it down to the grass-root level. This review discusses the contribution of sub-Saharan Africa, whose population is in a health transition, to malaria elimination. In addition, the review explores the challenges that health systems in these countries face, that may hinder the attainment of a zero-malaria goal.

PMID:36333802 | DOI:10.1186/s12936-022-04340-1

Pharmacogenomics J. 2022 Nov 4. doi: 10.1038/s41397-022-00294-4. Online ahead of print.

ABSTRACT

Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005-2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR] = 1.3, 95% CI = 1.04-1.62, p = 0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR = 1.46, 95% CI = 1.05-2.02, p = 0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.

PMID:36333412 | DOI:10.1038/s41397-022-00294-4

Nat Commun. 2022 Nov 4;13(1):6619. doi: 10.1038/s41467-022-34395-2.

ABSTRACT

Cancer-associated fibroblasts (CAFs) are the predominant components of the tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous characteristics across different cancer types. Here, we perform pan-cancer analysis on 226 samples across 10 solid cancer types to profile the TME at single-cell resolution, illustrating the commonalities/plasticity of heterogenous CAFs. Activation trajectory of the major CAF types is divided into three states, exhibiting distinct interactions with other cell components, and relating to prognosis of immunotherapy. Moreover, minor CAF components represent the alternative origin from other TME components (e.g., endothelia and macrophages). Particularly, the ubiquitous presentation of endothelial-to-mesenchymal transition CAF, which may interact with proximal SPP1+ tumor-associated macrophages, is implicated in endothelial-to-mesenchymal transition and survival stratifications. Our study comprehensively profiles the shared characteristics and dynamics of CAFs, and highlight their heterogeneity and plasticity across different cancer types. Browser of integrated pan-cancer single-cell information is available at https://gist-fgl.github.io/sc-caf-atlas/ .

PMID:36333338 | DOI:10.1038/s41467-022-34395-2

Lancet. 2022 Nov 1:S0140-6736(22)01655-5. doi: 10.1016/S0140-6736(22)01655-5. Online ahead of print.

ABSTRACT

Type 2 diabetes accounts for nearly 90% of the approximately 537 million cases of diabetes worldwide. The number affected is increasing rapidly with alarming trends in children and young adults (up to age 40 years). Early detection and proactive management are crucial for prevention and mitigation of microvascular and macrovascular complications and mortality burden. Access to novel therapies improves person-centred outcomes beyond glycaemic control. Precision medicine, including multiomics and pharmacogenomics, hold promise to enhance understanding of disease heterogeneity, leading to targeted therapies. Technology might improve outcomes, but its potential is yet to be realised. Despite advances, substantial barriers to changing the course of the epidemic remain. This Seminar offers a clinically focused review of the recent developments in type 2 diabetes care including controversies and future directions.

PMID:36332637 | DOI:10.1016/S0140-6736(22)01655-5

Hum Genet. 2022 Nov 4. doi: 10.1007/s00439-022-02480-7. Online ahead of print.

ABSTRACT

Rapid advancements of genome sequencing (GS) technologies have enhanced our understanding of the relationship between genes and human disease. To incorporate genomic information into the practice of medicine, new processes for the analysis, reporting, and communication of GS data are needed. Blood samples were collected from adults with a PCR-confirmed SARS-CoV-2 (COVID-19) diagnosis (target N = 1500). GS was performed. Data were filtered and analyzed using custom pipelines and gene panels. We developed unique patient-facing materials, including an online intake survey, group counseling presentation, and consultation letters in addition to a comprehensive GS report. The final report includes results generated from GS data: (1) monogenic disease risks; (2) carrier status; (3) pharmacogenomic variants; (4) polygenic risk scores for common conditions; (5) HLA genotype; (6) genetic ancestry; (7) blood group; and, (8) COVID-19 viral lineage. Participants complete pre-test genetic counseling and confirm preferences for secondary findings before receiving results. Counseling and referrals are initiated for clinically significant findings. We developed a genetic counseling, reporting, and return of results framework that integrates GS information across multiple areas of human health, presenting possibilities for the clinical application of comprehensive GS data in healthy individuals.

PMID:36331656 | DOI:10.1007/s00439-022-02480-7

Pharmacogenomics. 2022 Nov 4. doi: 10.2217/pgs-2022-0142. Online ahead of print.

NO ABSTRACT

PMID:36331025 | DOI:10.2217/pgs-2022-0142

Eur J Pharmacol. 2022 Oct 28;936:175356. doi: 10.1016/j.ejphar.2022.175356. Online ahead of print.

ABSTRACT

Type 2 Diabetes mellitus (T2DM) is a multifactorial metabolic disorder also known as a silent killer disease. Macrovascular and microvascular complications associated with diabetes worsen the condition leading to higher comorbidity and mortality rate. Currently, available treatment strategies for diabetes include biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, insulin and its analogs, DPP-4 (dipeptidyl-peptidase-4) inhibitors, SGLT-2 inhibitors, and Glucagon Like Peptide-1 receptor agonists (GLP-1RAs). Synthetic agonists of GLP-1 hormone, GLP-1RAs are an emerging class of anti-diabetic drugs which target the pathophysiology of diabetes through various mechanisms and at multiple sites. They promote insulin secretion from beta cells, and the proliferation of beta cells inhibits glucagon secretion, delays gastric emptying and induces satiety. However, treatment is reported to be associated with inter-individual variations and adverse drug reactions, which are also influenced by genetic variations. There have been a few pharmacogenetic studies have been carried out on this drug class. This review discusses all the available GLP-1RAs, their pharmacokinetics, pharmacodynamics and genetic variation affecting the inter-individual variation.

PMID:36330902 | DOI:10.1016/j.ejphar.2022.175356

Ann Transl Med. 2022 Oct;10(19):1048. doi: 10.21037/atm-22-4343.

NO ABSTRACT

PMID:36330391 | PMC:PMC9622471 | DOI:10.21037/atm-22-4343

Cardiovasc Diagn Ther. 2022 Oct;12(5):635-645. doi: 10.21037/cdt-22-154.

ABSTRACT

BACKGROUND: The implementation of genotyping for anti-hypertensive drugs in clinical practice remains a challenge. We conducted this study to analyze the distribution of polymorphisms of antihypertensive drug-related genes in Changsha County in China and compare the clinical effectiveness of genotype-guided and clinical experience-guided antihypertensive therapy in hypertensive individuals.

METHODS: A total of 9,933 essential hypertensive participants from Changsha County were consecutively enrolled in our study, and 7 genetic polymorphic loci (CYP2D6*10, ADRB1, CYP2C9*3, AGTR1, ACE, CYP3A5*3 and NPPA) were detected by a polymerase chain reaction (PCR)-fluorescence probe. From an available sample of 660 hypertensive participants, 495 cases were randomly identified by genotype-guided therapy and 165 cases by clinical experience-guided therapy. We performed 24-hour ambulatory blood pressure (BP) monitoring on each of these cases, pre- and post-intervention.

RESULTS: In the enrolled 9,933 cases, the mutation frequencies of CYP2C9*3, ADRB1(1165G>C), AGTR1(1166A>C), CYP2D6*10, ACE(I/D), CYP3A5*3 and NPPA(2238T>C) were 4.41%, 74.60%, 5.55%, 57.08%, 30.94%, 69.03% and 1.19%, respectively. In both genotype-guided and clinical experience-guided groups, the comparisons of intra-group pre-and post-treatments showed significant decreases in diastolic blood pressure (DBP) (P<0.01) and significant increases in the control rate of BP (47.1% vs. 38.6% and 37.5% vs. 33.9%, P<0.05) in response to adjusted antihypertensive agents. Correspondingly, the extent of the reduction of systolic blood pressure (SBP; 3.52±11.72 vs. 0.92±9.14 mmHg), the extent of the increase in the rate of BP control (8.5% vs. 3.6%) and the percentage rate of decrease of grades 2 and 3 hypertensive individuals were more significant in the genotype-guided group than that in the clinical experience-guided group (P<0.01).

CONCLUSIONS: While prescribing anti-hypertensive drugs, appropriate dosage and type adjustments should be made according to the gene mutation frequency and individual circumstances. Pharmacogenomics-guided personalized treatment of hypertensive patients is likely to be a more effective strategy, especially in those with significantly elevated SBP.

PMID:36329971 | PMC:PMC9622397 | DOI:10.21037/cdt-22-154