Personalizing Amlodipine Therapy in Hypertension The Role of Genetic Variants and Population-Specific Responses

Б  том ХXXI, 2025, № 2 ДРУЖЕСТВО НА КАРДИОЛОЗИТЕ В БЪЛГАРИЯ АВТОРСКИ СТАТИИ ORIGINAL ARTICLES PERSONALIZING AMLODIPINE THERAPY IN HYPERTENSION THE ROLE PERSONALIZING AMLODIPINE THERAPY IN HYPERTENSION THE ROLE OF GENETIC VARIANTS AND POPULATION-SPECIFIC RESPONSES OF GENETIC VARIANTS AND POPULATION-SPECIFIC RESPONSES D. P. Amukti1, R. I. Pratami2 1Department of Pharmacy, Faculty of Health Sciences, Alma Ata University 2Faculty of Pharmacy, University Ahmad Dahlan, Yogyakarta, Indonesia ПЕРСОНАЛИЗИРАНЕ НА ТЕРАПИЯТА С АМЛОДИПИН ПРИ ХИПЕРТОНИЯ – ПЕРСОНАЛИЗИРАНЕ НА ТЕРАПИЯТА С АМЛОДИПИН ПРИ ХИПЕРТОНИЯ – РОЛЯТА НА ГЕНЕТИЧНИТЕ ВАРИАНТИ И СПЕЦИФИЧНИТЕ РЕАКЦИИ РОЛЯТА НА ГЕНЕТИЧНИТЕ ВАРИАНТИ И СПЕЦИФИЧНИТЕ РЕАКЦИИ НА НАСЕЛЕНИЕТО НА НАСЕЛЕНИЕТО Д. П. Амукти1, Р. И. Прамати2 1Катедра по фармация, Факултет по здравни науки, Университет Алма Ата 2Факултет по фармация, Университет Ахмад Далан, Джокякарта, Индонезия Abstract. Introduction: Amlodipine is a long-acting dihydropyridine calcium channel blocker used in hypertension management. Despite its widespread use, therapeutic response varies signifi cantly among individuals, infl uenced by genetic, environmental, and physiological factors. Pharmacogenomics, which studies genetic variation affecting drug responses, has identifi ed specifi c genetic variants associated with amlodipine metabolism and effi cacy. Genes such as CYP3A4, RYR3, CACNA1C, and CACNA1D are known to play a role in amlodipine’s pharmacokinetics and pharmacodynamics. This review examines these genetic variants and their impact on amlodipine effi cacy, with a focus on populationspecifi c responses. Material and methods: This study utilized publicly available pharmacogenomic data from the PharmGKB and GTEx Portal to identify genetic variants associated with amlodipine effi cacy. Genetic variants from CYP3A4, RYR3, CACNA1C, and CACNA1D were selected based on their association with amlodipine response. Population-specifi c variations were also analyzed to assess differences in therapeutic outcomes across diverse biogeographical groups. Results: Seven single nucleotide polymorphisms (SNPs) from four genes were identifi ed: CYP3A4 (rs2246709, rs2740574), RYR3 (rs877087), CACNA1C (rs2239050, rs2239128), and CACNA1D (rs312481). SNPs such as rs2246709 in CYP3A4 and rs877087 in RYR3 were linked to enhanced amlodipine effi cacy in certain populations, while rs2740574 showed greater response in women. Variants like rs2239050 and rs312481 infl uenced amlodipine response in Central/South Asian and European populations. Conclusion: Genetic variants, including CYP3A4 (rs2246709, rs2740574), RYR3 (rs877087), CACNA1C (rs2239050, rs2239128), and CACNA1D (rs312481), signifi cantly infl uence amlodipine effi cacy in hypertensive patients. These fi ndings underscore the importance of genetic factors in personalizing hypertension treatment and optimizing drug effi cacy across diverse populations. However, further clinical validation and mechanistic studies are necessary to confi rm the therapeutic implications of these genetic associations. Understanding the distribution of these variants across populations may aid in tailoring amlodipine therapy based on ethnic and geographical factors, ensuring a more precise and effective treatment approach. Key words: hypertension, amlodipine, pharmacogenomics, genetic variants, CYP3A4, RYR3, CACNA1C, CACNA1D, single nucleotide polymorphisms, drug effi cacy, population-specifi c response, calcium channel blocker, precision medicine Аddress for correspondence Danang Prasetyaning Amukti, e-mail: [email protected] Резюме.Въведение: Амлодипин е дългодействащ дихидропиридинов блокер на калциевите канали, използван за лечение на хипертония. Въпреки широката му употреба терапевтичният отговор варира значително при отделните индивиди, тъй като се влияе от генетични, екологични и физиологични фактори. Фармакогеномиката, която изучава генетичните вариации, влияещи върху лекарствените реакции, е идентифицирала специфични генетични варианти, свързани с метаболизма и ефикасността на амлодипин. Известно е, че гени като CYP3A4, RYR3, CACNA1C и CACNA1D играят роля във фармакокинетиката и фармакодинамиката на амлодипин. В този материал се разглеждат тези генетични варианти и тяхното въздействие върху ефикасността на амлодипин, като се акцентира върху специфичните за популацията реакции. Материал и методи: В това проучване бяха This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. doi: 10.3897/bgcardio.31.e145941 73 Personalizing amlodipine therapy in hypertension... I Hypertension is a leading global health concern, affecting over 1.3 billion people worldwide and contributing signifi cantly to cardiovascular diseases, stroke, and renal failure [1, 2]. Eff ective management of hypertension is critical to reducing morbidity and mortality rates [3]. Among the various antihypertensive agents, amlodipine, a long-acting dihydropyridine calcium channel blocker (CCB), is widely prescribed due to its proven effi cacy, tolerability, and ability to reduce blood pressure across diverse patient populations [4]. However, despite its broad clinical use, signifi cant interindividual variability exists in response to amlodipine therapy, which poses challenges for personalized hypertension management [5, 6]. This variability in therapeutic response is infl uenced by multiple factors, including age, sex, comorbidities, and environmental conditions. In recent years, genetic factors have emerged as crucial determinants of drug effi cacy and safety [7]. Pharmacogenomics, the study of how genes aff ect an individual’s response to drugs, has provided insights into the mechanisms underlying variable responses to antihypertensive therapies. Specifi c genetic variants in key genes, such as CYP3A4, RYR3, CACNA1C, and CACNA1D, have been identifi ed as playing a role in the metabolism, transport, and pharmacodynamic action of amlodipine [8, 9]. Population-specifi c diff erences further complicate the pharmacogenomics of amlodipine. Genetic variations can vary signifi cantly across biogeographical groups, infl uencing the drug’s effi cacy and risk of adverse eff ects. For example, certain alleles are more prevalent in African, European, or Asian populations, which may explain the observed diff erences in clinical outcomes [10, 11]. Understanding these associations is essential for developing targeted therapeutic strategies to optimize blood pressure control in diverse populations [12]. This review aims to explore the impact of genetic variants on amlodipine effi cacy in hypertensive patients, with a focus on population-specifi c responses. By analyzing pharmacogenomic data and biogeographical variations, we seek to provide a comprehensive understanding of the role of genetics in antihypertensive therapy. Such insights will pave the way for precision medicine approaches, ensuring that patients receive the most eff ective and personalized treatment for hypertension. M   Study Design This study adopts a bioinformatics-based approach to investigate the association between genetic variants and the effi cacy of amlodipine in hypertensive patients. Data was extracted from publicly available pharmacogenomic databases, including PharmGKB and Gtex Portal, to identify relevant genetic variants, their functional signifi - cance, and population-specifi c distributions [13, 14]. PharmGKB Database PharmGKB (Pharmacogenomics Knowledge Base) was utilized to extract pharmacogenomic inforизползвани публично достъпни фармакогеномни данни от порталите PharmGKB и GTEx, за да се идентифицират генетични варианти, свързани с ефикасността на амлодипин. Специфичните за популацията вариации също бяха анализирани, за да се оценят разликите в терапевтичните резултати в различните биогеографски групи. Резултати: Бяха установени седем единични нуклеотидни полиморфизма (SNP) от четири гена: CYP3A4 (rs2246709, rs2740574), RYR3 (rs877087), CACNA1C (rs2239050, rs2239128) и CACNA1D (rs312481). SNP като rs2246709 в CYP3A4 и rs877087 в RYR3 са свързани с повишена ефикасност на амлодипин в определени популации, докато rs2740574 показва по-голям отговор при жените. Варианти като rs2239050 и rs312481 са повлияли на отговора на амлодипин при популации от Централна/Южна Азия и Европа. Заключение: Генетичните варианти, включително CYP3A4 (rs2246709, rs2740574), RYR3 (rs877087), CACNA1C (rs2239050, rs2239128) и CACNA1D (rs312481), оказват значително влияние върху ефикасността на амлодипин при пациенти с хипертония. Тези констатации подчертават значението на генетичните фактори за персонализиране на терапията при хипертония и за оптимизиране на ефикасността на лекарствата при различни популации. Въпреки това са необходими допълнителни клинични валидирания и механистични проучвания, за да се потвърдят терапевтичните последици от тези генетични асоциации. Разбирането на разпределението на тези варианти сред популациите може да помогне за адаптиране на терапията с амлодипин въз основа на етнически и географски фактори, като се гарантира по-прецизен и ефективен подход към лечението. Ключови думи:хипертония, амлодипин, фармакогеномика, генетични варианти, CYP3A4, RYR3, CACNA1C, CACNA1D, единични нуклеотидни полиморфизми, лекарствена ефикасност, специфичен за популацията отговор, блокер на калциевите канали, прецизна медицина Адрес за кореспонденция:Дананг Прасетянинг Амукти, e-mail: [email protected] D. P. Amukti, R. I. Pratami 74 mation related to amlodipine. Pharmacogenomic associations were identifi ed based on drug effi cacy, genetic variant annotations, and related clinical outcomes. Search terms: “Amlodipine”, “Hypertension”, “Genetic variants”, “Population responses”. Filters Focused on effi cacy outcomes and clinically relevant pharmacogenomic evidence.1516 GTEx Portal The GTEx (Genotype-Tissue Expression) Portal was used to analyze the expression levels of the genes associated with amlodipine effi cacy across diff erent tissues. Comparative analysis of expression levels was conducted to assess tissue-specifi c gene activity and its potential role in drug response [17, 18]. Data Analysis Variant Selection: Genetic variants were fi ltered based on their association with amlodipine effi cacy (P-value < 0.05). Variants were prioritized based on their functional annotations (eg, coding regions, regulatory impact) [19, 20]. Population-Specifi c Analysis: Frequency data for the selected variants were extracted from PharmGKB and cross-referenced with biogeographical groups (eg, African, Asian, European) to evaluate diff erences in genetic variant distributions15. Data Visualization: Results were presented using tables, heatmaps, and bar charts to illustrate variant distributions, functional impacts, and gene expression patterns across populations and tissues. R The search for genes related to amlodipine response in the PharmGKB database resulted in 30 relevant genes. After elimination based on p-values greater than 0.05, and selection based on drug effi cacy categories, only genes that showed signifi cant potential in therapeutic response were retained. Identifi cation of genetic variants associated with response to amlodipine in hypertension This selection process resulted in 7 SNPs originating from 4 genes in Table 1 and 2. These genes were then taken and further analyzed to evaluate their role in infl uencing the eff ectiveness of amlodipine therapy in hypertensive patients. This further analysis is expected to reveal deep genetic relationships and improve understanding of more personalized therapy for hypertension. Fig. 1. Research method fl owchart Created in https://BioRender.com Table 1. Genetic variants associated with response to amlodipine in hypertension Genes Variants P-Value Cases CYP3A4 rs2246709 0.01 145 RYR3 rs877087 0.04 1940 CYP3A4 rs2740574 0.02 61 CACNA1C rs2239050 0.024 200 CACNA1C rs2239050 0.05 53 CACNA1C rs2239128 0.04 53 CACNA1D rs312481 0.024 200 75 Personalizing amlodipine therapy in hypertension... Analysis of CYP3A4, RYR3, CACNA1D, CACNA1 gene expression in tissues and its relationship with the eff ectiveness of amlodipine in hypertension Amlodipine is a widely used calcium channel blocker and is eff ective in managing hypertension. However, interindividual variability in drug response is infl uenced by genetic factors. This analysis explores the tissue-specifi c expression of CYP3A4, RYR3, CACNA1D, and CACNA1 genes, focusing on their functional roles in pharmacokinetics. and pharmacodynamics of amlodipine (Fig. 2). The CYP3A4 gene is mainly expressed in the liver and small intestine, which plays an important role in amlodipine metabolism [21]. High hepatic expression facilitates the biotransformation of amlodipine to its inactive metabolites. Variability in CYP3A4 expression can alter drug plasma levels, aff ecting therapeutic outcomes. For Table 2. Association of Gene Variants with Amlodipine Effi cacy in Diff erent Ethnic Groups and Phenotype Categories Drugs Variants Association Biogeographical Groups Phenotype Categories Amlodipine rs2246709 Genotypes AG + GG are associated with increased response to amlodipine in people with hypertension as compared to genotype AA. African American/Afro-Caribbean Effi cacy Amlodipine rs877087 The TT genotype is associated with increased risk of Heart Failure when treated with amlodipine in people with Hypertension. Multiple groups, 64.7% White, 32.1% Black, 0.3% American Indian/Alaskan native, 0.9% Asian/Pacifi c Islander, 2.1% other, 11.5% Hispanic Effi cacy Amlodipine rs2740574 Genotypes CT + TT are associated with increased response to amlodipine in women with hypertension as compared to genotype CC. African American/Afro-Caribbean Effi cacy Amlodipine rs2239050 Genotype GG is associated with increased clinical benefi t to amlodipine in people with Hypertension as compared to genotypes CC + CG. Central/South Asian Effi cacy Amlodipine rs2239050 Genotype GG is associated with increased response to amlodipine and felodipine in people with hypertension as compared to genotype CG. European Effi cacy Amlodipine rs2239128 Allele C is associated with increased response to amlodipine and felodipine in people with Hypertension as compared to allele T. European Effi cacy Amlodipine rs312481 Genotype GG is associated with increased clinical benefi t to amlodipine in people with hypertension as compared to genotypes AA + AG. Central/South Asian Effi cacy Fig. 2. CYP3A4 gene expression in human body tissues D. P. Amukti, R. I. Pratami 76 example, lower CYP3A4 activity may result in a longer drug half-life and increased effi cacy or side eff ects. RYR3 Gene Expression and Calcium Signaling [22]. The RYR3 gene encodes a ryanodine receptor that plays a key role in the release of intracellular calcium from the sarcoplasmic reticulum [23, 24]. This pathway is a key component in the regulation of smooth muscle contraction, including vascular smooth muscle, which is the primary target of amlodipine [25]. Expression analysis results showed that the highest expression of the RYR3 gene was found in the uterus, followed by other smooth muscle tissues. This high expression in the uterus refl ects the physiological need for regulation of muscle contraction for reproductive function, which requires coordinated intracellular calcium release [26]. Relevance to Vascular Smooth Muscle: Although the highest expression is found in the uterus, RYR3 is also expressed in vascular smooth muscle. In the context of hypertension, RYR3 expression in vascular smooth muscle is of particular importance because modulation of this calcium pathway aff ects vascular tone and blood pressure [27]. Eff ects on Response to Amlodipine. High Expression: Increased expression of RYR3 in vascular smooth muscle may increase sensitivity to amlodipine, because ryanodine receptors promote calcium release that is the target of L-type calcium channel blockade. This may enhance the vasodilatory eff ect. Low Expression: Conversely, if RYR3 expression is reduced, the response to amlodipine may be weakened, reducing the drug’s eff ectiveness in lowering blood pressure [28]. Fig. 3. RYR3 gene expression in human body tissues Fig. 4. CACNA1D gene expression in human body tissues 77 Personalizing amlodipine therapy in hypertension... The CACNA1D gene encodes the alpha-1 subunit of the L-type calcium channel, which is the primary target of amlodipine [29]. This channel plays an important role in regulating the entry of calcium ions into cells, which aff ects smooth muscle contraction and cellular electrophysiological function [30]. Expression analysis showed that the highest expression of CACNA1D was found in the cervix, accompanied by signifi cant expression levels in cardiovascular tissues, such as the heart and blood vessels [31, 32]. Expression in the Cervix: High expression of CACNA1D in the cervix is likely related to the need for regulation of cervical smooth muscle contractions, especially in the context of reproductive functions such as labor. The role of L-type calcium channels in this tissue is to mediate coordinated calcium responses to physiological stimuli. Expression in Cardiovascular Tissues: In blood vessels and the heart, CACNA1D expression determines the eff ectiveness of L-type calcium channel blockade by amlodipine. These channels contribute directly to the regulation of vascular resistance and blood pressure. Relationship to Amlodipine Effi cacy CACNA1D expression in cardiovascular tissues is an important factor in determining the clinical response to amlodipine: High Expression in Blood Vessels Increases sensitivity to calcium channel blockade, thereby enhancing the vasodilatory eff ect and lowering blood pressure. Low Expression in Blood Vessels May result in a weaker response to amlodipine, reducing the drug’s eff ectiveness in lowering blood pressure [33]. The CACNA1 gene encodes an additional subunit of the L-type calcium channel, which supports the stability and function of the channel, including in response to amlodipine [34]. Analysis showed the highest expression of this gene in the colon, refl ecting its important role in the regulation of gastrointestinal smooth muscle motility. Although expression in the colon is not directly related to blood pressure regulation, CACNA1 expression in cardiovascular tissues, such as blood vessels, supports the effi cacy of amlodipine by enhancing the function of calcium channels in reducing vascular resistance. Optimal expression levels may increase sensitivity to amlodipine, while low expression may reduce drug effi cacy. In addition, expression in the colon may provide insight into potential gastrointestinal side eff ects of amlodipine use [35]. D Amlodipine works by inhibiting L-type calcium channels, which are regulated by genes such as CACNA1D and metabolized by the enzyme CYP3A4. This mechanism decreases peripheral vascular resistance, leading to lower blood pressure. However, the response to amlodipine varies signifi cantly between individuals, which is largely due to genetic diff erences. Several genetic variants have been identifi ed as determinants of response to amlodipine, including rs2246709, rs877087, rs2740574, and rs2239050, with diff erent eff ects on effi cacy and potential side eff ects. Several genetic variants have been identifi ed to infl uence individual responses to amlodipine in hypertensive patients. The AG + GG genotype at rs2246709 in African-American/Afro-Caribbeans showed a better hypertensive response than the AA genotype, indicating an infl uence of this variation on calcium channel expression or function. In [36] contrast, the TT genotype at rs877087 found in diverse populations was associated with an increased risk of heart failure in hypertensive patients receiving amlodipine, refl ecting a potential specifi c genetic side eff ect that requires clinical attention. In African-American/Afro-Caribbean women, Fig. 5. CACNA1 gene expression in human body tissues D. P. Amukti, R. I. Pratami 78 the CT + TT genotype at rs2740574 conferred a more optimal hypertensive response than the CC genotype, most likely through modulation of CYP3A4 metabolizing enzyme activity [37]. Other genetic variations, such as the GG genotype at rs2239050, are associated with increased clinical benefi t to amlodipine in Central/South Asian and European populations, suggesting that these variations may enhance drug effi cacy through mechanisms aff ecting calcium channel transport or interactions. In Europeans, the C allele at rs2239128 increases the response to amlodipine and felodipine compared to the T allele, likely due to diff erences in calcium channel affi nity [38]. In addition, the GG genotype at rs312481, which is common in Central/South Asians, is associated with greater clinical benefi t compared to the AA + AG genotypes, suggesting a link to blood pressure regulation [39]. These variations highlight the importance of considering genetic factors in personalizing hypertension therapy with amlodipine [40, 41]. In terms of pharmacodynamics, CACNA1C and CACNA1D regulate the L-type calcium channels, which are the primary targets of amlodipine. SNPs such as rs2239050 (GG genotype) in Central/South Asian and European populations have been associated with increased drug effi cacy, possibly due to enhanced calcium channel inhibition [31, 32]. Similarly, the C allele at rs2239128 is linked to greater response to amlodipine and felodipine in European populations, suggesting an eff ect on channel binding affi nity. Moreover, variations in RYR3 may contribute to adverse eff ects in certain individuals. The TT genotype at rs877087 has been associated with an increased risk of heart failure in hypertensive patients receiving amlodipine, potentially due to altered calcium signaling, which aff ects cardiac contractility. This suggests that pharmacogenomic screening could help identify patients at risk of cardiovascular side eff ects when prescribed amlodipine [39]. The diff erent distribution of genetic variants across populations suggests that strategies for personalizing amlodipine therapy should be tailored based on ethnic and geographic factors. For example, SNPs associated with increased response to amlodipine are more common in Asian populations, which may provide a basis for considering dose adjustments or more appropriate antihypertensive therapy choices for these populations. Although associations between genetic variants and response to amlodipine have been identifi ed, further validation through clinical studies is needed to confi rm their therapeutic implications. Patient-based pharmacokinetic and pharmacodynamic studies would be helpful in confi rming the specifi c role of the identifi ed SNPs in drug metabolism and effi cacy. C Genetic variants of CYP3A4 (rs2246709, rs2740574), RYR3 (rs877087), CACNA1C (rs2239050, rs2239128), and CACNA1D (rs312481) play a role in determining the eff ectiveness of amlodipine in hypertensive patients. 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