Pharmacy (Basel). 2023 Aug 8;11(4):125. doi: 10.3390/pharmacy11040125.

ABSTRACT

BACKGROUND: There is a paucity of evidence to inform the value of pharmacogenomic (PGx) results in patients after kidney transplant and how these results differ between Indigenous Americans and Whites. This study aims to identify the frequency of recommended medication changes based on PGx results and compare the pharmacogenomic (PGx) results and patients' perceptions of the findings between a cohort of Indigenous American and White kidney transplant recipients.

METHODS: Thirty-one Indigenous Americans and fifty White kidney transplant recipients were studied prospectively. Genetic variants were identified using the OneOme RightMed PGx test of 27 genes. PGx pharmacist generated a report of the genetic variation and recommended changes. Pre- and post-qualitative patient surveys were obtained.

RESULTS: White and Indigenous American subjects had a similar mean number of medications at the time of PGx testing (mean 13 (SD 4.5)). In the entire cohort, 53% received beta blockers, 30% received antidepressants, 16% anticoagulation, 47% pain medication, and 25% statin therapy. Drug-gene interactions that warranted a clinical action were present in 21.5% of patients. In 12.7%, monitoring was recommended. Compared to the Whites, the Indigenous American patients had more normal CYP2C19 (p = 0.012) and CYP2D6 (p = 0.012) activities. The Indigenous American patients had more normal CYP4F2 (p = 0.004) and lower VKORC (p = 0.041) activities, phenotypes for warfarin drug dosing, and efficacy compared to the Whites. SLC6A4, which affects antidepressant metabolism, showed statistical differences between the two cohorts (p = 0.017); specifically, SLC6A4 had reduced expression in 45% of the Indigenous American patients compared to 20% of the White patients. There was no significant difference in patient perception before and after PGx.

CONCLUSIONS: Kidney transplant recipients had several drug-gene interactions that were clinically actionable; over one-third of patients were likely to benefit from changes in medications or drug doses based on the PGx results. The Indigenous American patients differed in the expression of drug-metabolizing enzymes and drug transporters from the White patients.

PMID:37624080 | DOI:10.3390/pharmacy11040125

J Pers Med. 2023 Jul 28;13(8):1201. doi: 10.3390/jpm13081201.

ABSTRACT

BACKGROUND: Previous studies have documented pain as an important concern for quality of life (QoL) and one of the most challenging manifestations for cancer patients. Thus, cancer pain management (CPM) plays a key role in treating pain related to cancer. The aim of this systematic review was to investigate CPM, with an emphasis on personalized medicine, and introduce new pharmacogenomics-based procedures for detecting and treating cancer pain patients.

METHODS: This study systematically reviewed PubMed from 1990 to 2023 using keywords such as cancer, pain, and personalized medicine. A total of 597 publications were found, and after multiple filtering processes, 75 papers were included. In silico analyses were performed using the GeneCards, STRING-MODEL, miRTargetLink2, and PharmGKB databases.

RESULTS: The results reveal that recent reports have mainly focused on personalized medicine strategies for CPM, and pharmacogenomics-based data are rapidly being introduced. The literature review of the 75 highly relevant publications, combined with the bioinformatics results, identified a list of 57 evidence-based genes as the primary gene list for further personalized medicine approaches. The most frequently mentioned genes were CYP2D6, COMT, and OPRM1. Moreover, among the 127 variants identified through both the literature review and data mining in the PharmGKB database, 21 variants remain as potential candidates for whole-exome sequencing (WES) analysis. Interestingly, hsa-miR-34a-5p and hsa-miR-146a-5p were suggested as putative circulating biomarkers for cancer pain prognosis and diagnosis.

CONCLUSIONS: In conclusion, this study highlights personalized medicine as the most promising strategy in CPM, utilizing pharmacogenomics-based approaches to alleviate cancer pain.

PMID:37623452 | DOI:10.3390/jpm13081201

J Pers Med. 2023 Jul 26;13(8):1185. doi: 10.3390/jpm13081185.

ABSTRACT

Pharmacogenomics may improve patient care by guiding drug selection and dosing; however, this requires prior knowledge of the pharmacogenomics of drugs commonly used in a specific setting. The aim of this study was to identify a preliminary set of pharmacogenetic variants important in Southern Africa. We describe comorbidities in 3997 patients from Malawi, South Africa, and Zimbabwe. These patient cohorts were included in pharmacogenomic studies of anticoagulation, dyslipidemia, hypertension, HIV and breast cancer. The 20 topmost prescribed drugs in this population were identified. Using the literature, a list of pharmacogenes vital in the response to the top 20 drugs was constructed leading to drug-gene pairs potentially informative in translation of pharmacogenomics. The most reported morbidity was hypertension (58.4%), making antihypertensives the most prescribed drugs, particularly amlodipine. Dyslipidemia occurred in 31.5% of the participants, and statins were the most frequently prescribed as cholesterol-lowering drugs. HIV was reported in 20.3% of the study participants, with lamivudine/stavudine/efavirenz being the most prescribed antiretroviral combination. Based on these data, pharmacogenes of immediate interest in Southern African populations include ABCB1, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLC22A1, SLCO1B1 and UGT1A1. Variants in these genes are a good starting point for pharmacogenomic translation programs in Southern Africa.

PMID:37623436 | DOI:10.3390/jpm13081185

Curr Issues Mol Biol. 2023 Aug 7;45(8):6550-6563. doi: 10.3390/cimb45080413.

ABSTRACT

The study of anaemia is a well-developed discipline where the concepts of precision medicine have, in part, been researched extensively. This review discusses the treatment of erythropoietin (EPO) deficiency anaemia and resistance in cases of chronic kidney disease (CKD). Traditionally, erythropoietin-stimulating agents (ESAs) and iron supplementation have been used to manage anaemia in cases of CKD. However, these treatments pose potential risks, including cardiovascular and thromboembolic events. Newer treatments have emerged to address these risks, such as slow-release and low-dosage intravenous iron, oral iron supplementation, and erythropoietin-iron combination therapy. Another novel approach is the use of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). This review highlights the need for precision medicine targeting the genetic components of EPO deficiency anaemia in CKD and discusses individual variability in genes such as the erythropoietin gene (EPO), the interleukin-β gene (IL-β), and the hypoxia-inducible factor gene (HIF). Pharmacogenetic testing aims to provide targeted therapies and interventions that are tailored to the specific characteristics of an individual, thus optimising treatment outcomes and minimising resistance and adverse effects. This article concludes by suggesting that receptor modification has the potential to revolutionise the treatment outcomes of patients with erythropoietin deficiency anaemia through the integration of the mentioned approach.

PMID:37623232 | DOI:10.3390/cimb45080413

Br J Clin Pharmacol. 2023 Aug 24. doi: 10.1111/bcp.15894. Online ahead of print.

ABSTRACT

AIM: Azathioprine (AZA) and 6-mercaptopurine (6MP) are prescribed in acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6-thioguanine (6TGN) and 6-methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation.

METHODS: The first paediatric TDM samples received during year 2021 were analyzed, whatever indication and thiopurine drug. Target concentration ranges were 200-500, <6000 pmol/8*108 RBC for 6TGN and 6MMPN.

RESULTS: Children (n=492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7 years in IBD (p<0.0001). ALL received 6MP (mean dose 1.7 mg/kg/d with methotrexate), IBD received AZA (1.9 mg/kg/d with anti-inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [IQR: 142.5; 309.6] and 1144.6 [IQR: 419.4; 3574.3] pmol/8*108 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine amino-transaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant.

CONCLUSION: TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow-up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome.

PMID:37621013 | DOI:10.1111/bcp.15894

Cell Mol Life Sci. 2023 Aug 24;80(9):265. doi: 10.1007/s00018-023-04901-w.

ABSTRACT

Transient receptor potential cation channel-6 (TRPC6) gene mutations cause familial focal segmental glomerulosclerosis (FSGS), which is inherited as an autosomal dominant disease. In patients with TRPC6-related FSGS, all mutations map to the N- or C-terminal TRPC6 protein domains. Thus far, the majority of TRPC6 mutations are missense resulting in increased or decreased calcium influx; however, the fundamental molecular mechanisms causing cell injury and kidney pathology are unclear. We report a novel heterozygous TRPC6 mutation (V691Kfs*) in a large kindred with no signs of FSGS despite a largely truncated TRPC6 protein. We studied the molecular effects of V691Kfs* TRPC6 mutant using the tridimensional cryo-EM structure of the tetrameric TRPC6 protein. The results indicated that V691 is localized at the pore-forming transmembrane region affecting the ion conduction pathway, and predicted that V691Kfs* causes closure of the ion-conducting pathway leading to channel inactivation. We assessed the impact of V691Kfs* and two previously reported TRPC6 disease mutants (P112Q and G757D) on calcium influx in cells. Our data show that the V691Kfs* fully inactivated the TRCP6 channel-specific calcium influx consistent with a complete loss-of-function phenotype. Furthermore, the V691Kfs* truncation exerted a dominant negative effect on the full-length TRPC6 proteins. In conclusion, the V691Kfs* non-functional truncated TRPC6 is not sufficient to cause FSGS. Our data corroborate recently characterized TRPC6 loss-of-function and gain-of-function mutants suggesting that one defective TRPC6 gene copy is not sufficient to cause FSGS. We underscore the importance of increased rather than reduced calcium influx through TRPC6 for podocyte cell death.

PMID:37615749 | DOI:10.1007/s00018-023-04901-w

Pharmacogenomics. 2023 Aug 24. doi: 10.2217/pgs-2023-0097. Online ahead of print.

ABSTRACT

Objective & methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes and SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e., CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (β-coefficient = 10.03; 95% CI: 1.42, 18.6; p = 0.025). In an exploratory analysis, participants with low CYP2C9 activity had lower anastrozole concentrations and higher fulvestrant concentrations than participants with high CYP2C9 activity. Conclusion: Inherited genetic variation in CYP3A4 and CYP2C9 may affect concentrations of endocrine therapy and may be useful to personalize dosing and improve treatment outcomes.

PMID:37615099 | DOI:10.2217/pgs-2023-0097

Front Pharmacol. 2023 Aug 8;14:1267344. doi: 10.3389/fphar.2023.1267344. eCollection 2023.

NO ABSTRACT

PMID:37614312 | PMC:PMC10442934 | DOI:10.3389/fphar.2023.1267344

Nat Commun. 2023 Aug 23;14(1):4863. doi: 10.1038/s41467-023-39858-8.

ABSTRACT

Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.

PMID:37612283 | DOI:10.1038/s41467-023-39858-8

Comput Biol Med. 2023 Aug 10;165:107329. doi: 10.1016/j.compbiomed.2023.107329. Online ahead of print.

ABSTRACT

Screening potential drug-drug interactions, drug-gene interactions, contraindications, and other factors is crucial in clinical practice. However, implementing these screening concepts in real-world settings poses challenges. This work proposes an approach towards precision medicine that combines genetic and nongenetic factors to facilitate clinical decision-making. The approach focuses on raising the performance of four potential interaction screenings in the prescribing process, including drug-drug interactions, drug-gene interactions, drug-herb interactions, drug-social lifestyle interactions, and two potential considerations for patients with liver or renal impairment. The work describes the design of a curated knowledge-based model called the knowledge model for potential interaction and consideration screening, the screening logic for both the detection module and inference module, and the personalized prescribing report. Three case studies have demonstrated the proof-of-concept and effectiveness of this approach. The proposed approach aims to reduce decision-making processes for healthcare professionals, reduce medication-related harm, and enhance treatment effectiveness. Additionally, the recommendation with a semantic network is suggested to assist in risk-benefit analysis when health professionals plan therapeutic interventions with new medicines that have insufficient evidence to establish explicit recommendations. This approach offers a promising solution to implementing precision medicine in clinical practice.

PMID:37611418 | DOI:10.1016/j.compbiomed.2023.107329

Pharmacogenomics. 2023 Aug 23. doi: 10.2217/pgs-2023-0103. Online ahead of print.

ABSTRACT

Background: This study investigated the use of COMT G1947A and OPRM1 A118G polymorphisms as predictive markers for sufentanil epidural analgesia. Methods: The visual analogue scale (VAS) score, and sufentanil consumption of 136 pairs of parturients using sufentanil with lidocaine and ropivacaine for epidural analgesia were used for analysis. Results: OPRM1 AG/GG had lower VAS score difference between fifth and 0 min (1.55 vs 1.87; p = 0.012) and higher consumption (19.65 μg vs 17.11 μg; p = 0.049) than AA carriers. COMT GA/AA had higher VAS score difference than GG carriers (1.86 vs 1.55; p = 0.021). Conclusion: Sufentanil may provide better epidural labor analgesia in OPRM1 AA and COMT GA/AA carriers compared with OPRM1 AG/GG and COMT GG carriers. Clinical Trial Registration: ChiCTR1900026897 (Chinese Clinical Trial Center Registry).

PMID:37610885 | DOI:10.2217/pgs-2023-0103

Pharmacogenomics. 2023 Aug 23. doi: 10.2217/pgs-2023-0109. Online ahead of print.

ABSTRACT

Metformin, a hypoglycemic drug for Type 2 diabetes mellitus, shows variability in pharmacokinetics and response due to membrane transporters. This study followed 34 Type 2 diabetes mellitus patients on metformin treatment. Genetic variants in 11 metformin transport-related genes were analyzed, revealing associations. Specifically, SLC47A1 rs2289669 A/A and SLC22A4 rs1050152 T/T genotypes correlated with glycated hemoglobin values at 6 months. SLC47A1 rs2289669 G/A genotype influenced glucose levels at 6 months, while SLC29A4 rs3889348 A/A, SLC47A1 rs2289669 A/A, SLC22A4 rs1050152 C/T and SLC47A2 rs12943590 A/A genotypes were linked to glucose levels at 12 months. Additionally, ABCB1 rs2032582 C/A and ABCG2 rs2231137 C/T genotypes impacted cholesterol levels at 12 months. These findings shed light on metformin response determinants, offering insights for further research.

PMID:37610884 | DOI:10.2217/pgs-2023-0109

Pharmacogenomics. 2023 Aug 23. doi: 10.2217/pgs-2023-0105. Online ahead of print.

ABSTRACT

Ethnicity is known to have an impact on drug responses. This is particularly important for drugs that have a narrow therapeutic window, nonlinearity in pharmacokinetics and are metabolized by enzymes that demonstrate genetic polymorphisms. However, most clinical trials are conducted among Caucasians, which might limit the usefulness of the findings of such studies for other ethnicities. The representation of participants from Saudi Arabia in global clinical trials is low. Therefore, there is a paucity of evidence to assess the impact of ethnic variability in the Saudi population on drug response. In this article, the authors assess the projected impact of genetic polymorphisms in drug-metabolizing enzymes and drug targets on drug response in the Saudi population.

PMID:37610881 | DOI:10.2217/pgs-2023-0105

Psychiatr Ann. 2021 Apr;51(4):175-184. doi: 10.3928/00485713-20210309-01.

ABSTRACT

Neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention-deficit/hyper-activity disorder (ADHD), represent a group of conditions that manifest early in child development and produce impairments across multiple domains of functioning. Although a number of pharmacological and psychosocial treatments exist to improve the symptoms associated with these syndromes, treatment advances have lagged. The Precision Medicine Initiative was launched with the goal of revolutionizing medicine by progressing beyond the historical one-size-fits-all approach. In this review, we evaluate current research efforts to personalize treatments for ASD and ADHD. Most pharmacogenetic testing has focused on the cytochrome P450 enzyme family with a particular focus on CYP2D6 and CYP2C19, which are genes that produce an enzyme that acts as a key metabolizer of many prescribed medications. This article provides an update on the state of the field of pharmacogenetics and "therapy-genetics" in the context of ASD and ADHD, and it also encourages clinicians to follow US Food and Drug Administration recommendations regarding pharmacogenetic testing.

PMID:37609560 | PMC:PMC10443929 | DOI:10.3928/00485713-20210309-01

Front Oncol. 2023 Aug 7;13:1232476. doi: 10.3389/fonc.2023.1232476. eCollection 2023.

ABSTRACT

[This corrects the article DOI: 10.3389/fonc.2022.979519.].

PMID:37609387 | PMC:PMC10441771 | DOI:10.3389/fonc.2023.1232476

Front Psychiatry. 2023 Aug 7;14:1250253. doi: 10.3389/fpsyt.2023.1250253. eCollection 2023.

ABSTRACT

BACKGROUND: Pharmacogenetic analyses can predict interpersonal differences in response to psychopharmacotherapy, which greatly facilitates the selection of the most effective medication at optimal doses. By personalizing therapy in this way, we can minimize adverse drug reactions (ADR) and prevent polypharmacy. Most psychotropic medications are metabolized by the cytochrome P450 enzymes CYP2D6, CYP2C19, and CYPA3A4, which influence drug metabolism and concentration, affecting both efficacy and the occurrence of ADR. The relationships between genetic variations and enzymatic activity allow pharmacogenetic analysis to provide important data for optimal drug selection. The following case report illustrates the impact of pharmacogenetic analysis on the course of pharmacologic treatment in an elderly patient with a major depressive episode.

METHODS: We present a case of a 79-year-old patient treated for severe depression with psychotic symptoms. We collected data on treatment selection and response to treatment before and after pharmacogenetic analysis. For pharmacogenetic analysis, common functional variants in CYP1A2, CYP3A4, CYP2B6, CYP2C19, and CYP2D6 were genotyped, and corresponding evidence-based treatment recommendations were prepared.

RESULTS: The patient suffered from lack of efficacy and serious ADR of several medications, resulting in worsening depression and treatment resistance over the course of several months of treatment. Pharmacogenetic analysis provided important insights into the patient's pharmacokinetic phenotype and allowed us to personalize treatment and achieve remission of the depressive episode.

CONCLUSION: In the case presented, we have shown how consideration of pharmacogenetic characteristics in an individual patient can improve treatment outcome and patient well-being. Knowledge of the patient's pharmacogenetic characteristics helped us to personalize treatment, resulting in complete remission of psychopathology. Due to the complexity of psychiatric disorders, the efficacy of combinations of different medications, which are often required in individual patients, cannot be clearly explained. Therefore, it is of great importance to conduct further pharmacokinetic and pharmacogenetic studies to better assess gene-drug interactions in psychopharmacotherapy.

PMID:37608991 | PMC:PMC10440381 | DOI:10.3389/fpsyt.2023.1250253

Diabetes Obes Metab. 2023 Aug 22. doi: 10.1111/dom.15246. Online ahead of print.

ABSTRACT

AIM: To validate pharmacodynamic responses to sodium-glucose co-transporter-2 (SGLT2) inhibitors and test for association with genetic variants in SLC5A4, SLC5A9, and SLC2A9.

METHODS: Canagliflozin (300 mg), a SGLT2 inhibitor, was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses, including drug-induced increases in urinary excretion of glucose, sodium and uric acid.

RESULTS: This pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (-4.1 mg/dL; P = 6 × 10-5 ), serum creatinine (+0.05 mg/dL; P = 8 × 10-4 ) and serum uric acid (-0.90 mg/dL; P = 5 × 10-10 ). The effects of sex on glucosuria depended upon how data were normalized. Whereas males' responses were ~60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated glomerular filtration rate or age in those healthy individuals without diabetes with an estimated glomerular filtration rate of more than 60 mL/min/1.73m2 .

CONCLUSIONS: Normalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study (NCT02891954) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as HbA1c and renal function.

PMID:37608471 | DOI:10.1111/dom.15246

Methods Mol Biol. 2023;2967:181-192. doi: 10.1007/978-1-0716-3358-8_15.

ABSTRACT

Polymerase chain reaction (PCR) is a laboratory technique used to amplify a targeted region of DNA, demarcated by a set of oligonucleotide primers. Long-range PCR is a form of PCR optimized to facilitate the amplification of large fragments. Using the adapted long-range PCR protocol described in this chapter, we were able to generate PCR products of 6.6, 7.2, 13, and 20 kb from human genomic DNA samples. For some of the long PCRs, successful amplification was not possible without the use of PCR enhancers. Thus, we also evaluated the impact of some enhancers on long-range PCR and included the findings as part of this updated chapter.

PMID:37608112 | DOI:10.1007/978-1-0716-3358-8_15

Small. 2023 Aug 22:e2206688. doi: 10.1002/smll.202206688. Online ahead of print.

ABSTRACT

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer , accounting for approximately 85% of lung cancers. For more than 40 years, platinum (Pt)-based drugs are still one of the most widely used anticancer drugs even in the era of precision medicine and immunotherapy. However, the clinical limitations of Pt-based drugs, such as serious side effects and drug resistance, have not been well solved. This study constructs a new albumin-encapsulated Pt(IV) nanodrug (HSA@Pt(IV)) based on the Pt(IV) drug and nanodelivery system. The characterization of nanodrug and biological experiments demonstrate its excellent drug delivery and antitumor effects. The multi-omics analysis of the transcriptome and the ionome reveals that nanodrug can activate ferroptosis by affecting intracellular iron homeostasis in NSCLC. This study provides experimental evidence to suggest the potential of HSA@Pt(IV) as a nanodrug with clinical application.

PMID:37606911 | DOI:10.1002/smll.202206688

Acta Neuropsychiatr. 2023 Aug 22:1-35. doi: 10.1017/neu.2023.38. Online ahead of print.

ABSTRACT

OBJECTIVE: In Alzheimer's disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-β by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-β-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering APOE-ε4 carrier status and blood pressure response to angiotensin modulators.

METHODS: Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for one year, taking APOE-ε4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs.

RESULTS: For 193 patients (67.4% women, 53.4% APOE-ε4 carriers), the ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p=0.281), while arterial hypertension was prevalent in 80.3% (n=124 used an ACEi, n=21 used an ARB). ARBs benefitted mostly APOE-ε4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ε4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations.

CONCLUSION: Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

PMID:37605989 | DOI:10.1017/neu.2023.38