Pharmacogenetics and Pharmacogenomics Impact on Aspirin Response

Abstract

Aspirin, or Acetylsalicylic acid (ASA), is renowned for its pain-relieving and anti-inflammatory properties. Recent insights have illuminated its mechanisms and potential applications. Notably, low-dose aspirin reduces heart attack and stroke risks, particularly in high-risk individuals, yet optimal dosing remains under investigation. Another area explores aspirin’s potential in cancer prevention, especially for colon and gastrointestinal cancers, along with emerging roles against conditions like Alzheimer’s, diabetes, and pre-eclampsia. Aspirin’s benefits extend to kidney disease and COVID-19 research due to its anti-inflammatory actions. Stem cell effects are diverse; while enhancing hematopoietic stem cells aids bone marrow transplants, it may inhibit embryonic stem cells in specific contexts. However, challenges encompass resistance, allergies, gastrointestinal effects, and pediatric Reye’s syndrome. Pharmacogenetic studies illuminate how genetic variations impact aspirin metabolism, with enzymes like CYP2C9 and CYP2C19 affecting clearance rates, and markers such as P2RY12 and COX-1 influencing antiplatelet responses. Customized aspirin therapy, guided by genetic profiles, optimizes benefits and minimizes risks. This research underpins personalized medicine, empowering clinicians to enhance treatment precision, efficacy, and safety. As aspirin’s complex advantages and challenges continue to unfold, refined therapeutic strategies will emerge.

1. Introduction

Aspirin, scientifically known as Acetylsalicylic acid (ASA), is a widely used drug that serves multiple purposes, including pain relief, inflammation reduction, and blood clot risk reduction. As a Nonsteroidal anti-inflammatory drug (NSAID), Aspirin (Figure 1) works by inhibiting the production of specific molecules responsible for pain and inflammation. It finds extensive use in treating various conditions, such as menstrual cramps, toothaches, headaches, and fever [1].

Figure 1.

Chemical structure of aspirin.

The history of aspirin dates back to ancient civilizations, with ancient Sumerians and Egyptians using willow bark and leaves to address inflammatory diseases and alleviate joint pain. Hippocrates, the father of medicine, recommended using Cortex salicis for labor pain and ocular pain. In 1828, Professor Johann Buchner discovered salicin, a yellow bitter crystal extracted from willow bark, which was later converted to salicylic acid (SA) through various chemical processes. In 1838, the French chemist Charles Frederich Gerhardt successfully acetylated salicylic acid, producing ASA for the first time. However, it was only in 1899 that Bayer & Co. made ASA available in powder form, registering it under the name “Aspirin.” Today, aspirin is a widely recognized and essential medication, with an estimated annual consumption of 44,000 tonnes (50–120 billion pills), and it is listed on the World Health Organization’s list of essential medicines [2, 3].

Aspirin is available in various doses and forms, including chewable tablets, suppositories, and extended-release formulations. The two primary forms are enteric-coated and immediate-release aspirin. Immediate-release aspirin is quickly and completely absorbed after oral intake in the acidic conditions of the stomach and upper small intestine, resulting in a quick peak concentration. In contrast, enteric-coated aspirin is absorbed by the gastrointestinal mucosa due to the elevated pH in the small intestine, leading to a reduced bioavailability and slower peak concentration. Salicylate, the active component of aspirin, primarily binds to albumin in the blood and is mainly excreted through the kidneys as salicyluric acid. In cases of aspirin overdose, urinary alkalinization is used to promote salicylate elimination, as renal excretion of salicylic acid is sensitive to variations in urinary pH [4, 5].

Aspirin acts on its targets in the portal circulation, where platelets are exposed to a higher drug level than in the systemic circulation. Up to 80% of therapeutic doses of aspirin are metabolized (deactivated) in the liver. Although aspirin has a short half-life of 15 to 20 minutes, its pharmacodynamic effects on platelets last for the entire lifespan of platelets, which is approximately 7 to 10 days. This effect can only be countered by generating new platelets, although there are suggestions that ASA may have inhibitory effects on blood marrow megakaryocytes [6].

The irreversible acetylation of platelets by ASA can be inhibited by concurrent use of reversible COX-1 inhibitors, such as ibuprofen and naproxen, leading to a reduction in aspirin’s antiplatelet effects. Additionally, coadministering non-selective NSAIDs with aspirin can increase the risk of thrombotic and bleeding events [7, 8].

Aspirin’s primary application lies in preventing cardiovascular and cerebrovascular diseases, particularly in reducing the risk of heart attacks and strokes. It achieves this by inhibiting the function of thromboxane A2, which helps minimize the formation of blood clots [9, 10]. Aspirin’s effects, such as inflammation reduction, analgesia, clotting prevention, and fever reduction, are largely attributed to its impact on prostaglandin and thromboxane production, both derived from arachidonic acid. As the only NSAID capable of covalently acetylating and irreversibly inactivating both COX-1 and COX-2 enzyme isoforms, aspirin exhibits a unique pharmacological profile. COX-1 inhibition mainly leads to an antiplatelet effect, while COX-2 inhibition provides anti-inflammatory effects [11, 12].

The mechanism of action of aspirin involves irreversible acetylation of platelets, which inhibits cyclooxygenase (COX) enzymes, specifically COX-1 and COX-2. COX-1 inhibition mainly contributes to its antiplatelet effect, while COX-2 inhibition provides anti-inflammatory effects [13]. This property makes aspirin unique among NSAIDs. Its short half-life of 15 to 20 minutes belies its prolonged pharmacodynamic effects on platelets that last for the entire platelet lifespan (7 to 10 days) [14]. Because nucleated cells quickly resynthesize the enzyme, pathophysiologic processes that depend on COX-2 need for higher doses and a shorter dosing interval [15]. Reduced platelet aggregation can be achieved with low-dose ASA (75–80 mg). However, for anti-inflammatory activity, a greater dose (>325 mg) is required [16, 17].

Due to the substantial variability in individual responses to aspirin therapy, there is significant interest in exploring the pharmacogenetic and pharmacogenomic aspects of aspirin treatment. Pharmacogenetics and pharmacogenomics are fields that study how genetic variations influence drug metabolism, transport, and target interactions. These disciplines offer valuable insights into individual variations in drug efficacy, safety, and adverse reactions, paving the way for personalized medicine approaches in drug therapy [18].

The metabolism and bioactivation of aspirin are crucial factors in understanding its pharmacogenetic profile. Hepatic metabolism through ester hydrolysis leads to the formation of salicylic acid, the active metabolite responsible for aspirin’s therapeutic effects. Genetic polymorphisms in the CYP2C9 gene, a member of the cytochrome P450 family, significantly impact aspirin’s metabolism, leading to variations in drug levels and platelet inhibition. Patients with specific CYP2C9 variants may experience altered drug clearance, resulting in either reduced or enhanced platelet inhibition, with implications for the clinical response to aspirin therapy [19].

In addition to metabolism, the pharmacogenetic aspect of aspirin therapy also involves variations in the target receptor, cyclooxygenase (COX). Aspirin’s antiplatelet effects are mediated through the irreversible acetylation of a serine residue in the COX-1 enzyme, inhibiting its activity and preventing the production of thromboxane A2. Genetic variations in the COX-1 gene may influence the enzyme’s activity and alter the degree of platelet inhibition achieved with aspirin therapy. For instance, certain genetic variants have been associated with reduced COX-1 activity, potentially leading to suboptimal antiplatelet effects of aspirin in some individuals [20].

Furthermore, the emerging field of pharmacogenomics has provided new avenues to explore the genetic determinants of aspirin drug therapy. Genome-wide association studies (GWAS) have identified genetic loci associated with aspirin response, shedding light on novel pathways and biological processes that influence aspirin’s pharmacodynamics and pharmacokinetics. Pharmacogenomic investigations have uncovered gene-gene and gene-environment interactions that may impact aspirin therapy outcomes. These findings not only offer insights into aspirin’s individual variability but also pave the way for the development of more targeted and effective treatment approaches [21].

Understanding the genetic factors that influence aspirin metabolism and response can lead to more personalized and effective drug therapies, advancing the future of precision medicine in healthcare. In this chapter challenges, applications, Pharmacogenomics & Pharmacogenetics aspects related to aspirin are discussed.

2. Challenges in aspirin therapy

2.1 Aspirin sensitivity

Aspirin sensitivity, also known as an aspirin-related adverse event, can lead to various symptoms, including nasal congestion, runny nose, hives, and breathing difficulties. In severe cases, it may even cause anaphylaxis, a life-threatening allergic reaction [22]. There are two main mechanisms for aspirin sensitivity: non-immunologic reactions, primarily involving the inhibition of the cyclooxygenase (COX)-1 pathway, and immunological responses, which often require drug-specific IgE generation against the NSAID. Immunological reactions can lead to urticaria/angioedema and, in rare instances, anaphylaxis, while COX-1 inhibition by aspirin can cause respiratory issues [23].

To address aspirin sensitivity, desensitization therapy is commonly employed. The goal of desensitization is to reduce or eliminate adverse reactions when taking aspirin. This process involves starting with a small dose and gradually increasing it over time to help the individual’s body develop tolerance to the medication. It’s important to note that desensitization is not a cure, and some individuals may not respond well to it. People with aspirin-exacerbated respiratory disease (AERD), which involves asthma, nasal polyps, and aspirin sensitivity, as well as those with urticaria and Kawasaki disease, have been found to benefit from aspirin desensitization [24].

2.2 Aspirin resistance

Aspirin resistance refers to the failure of aspirin to decrease thromboxane A2 synthesis by platelets, leading to platelet activation and aggregation. This condition can be caused by various factors such as genetics, obesity, and specific medical disorders. Aspirin resistance may increase the risk of heart attack, stroke, and other thrombotic events. Laboratory tests are used to identify aspirin resistance by measuring platelet thromboxane A2 production or platelet function that relies on platelet thromboxane production. The underlying causes of aspirin resistance may include insufficient dosage, medication interactions, genetic polymorphisms in COX-1 and other thromboxane biosynthesis-related genes, overexpression of non-platelet sources of thromboxane production, and accelerated platelet turnover. Addressing the underlying cause can help reverse aspirin resistance. Research is ongoing to better understand this phenomenon and develop accurate diagnostics and potential treatments [25, 26].

2.3 Gastrointestinal problems

Aspirin is rapidly absorbed in the proximal small intestine and stomach. Factors such as the amount of fluid ingested with aspirin, the pH of the gastrointestinal tract, rate of gastric emptying, presence of food, and the type of aspirin formulation can affect its absorption. Taking aspirin after eating is recommended to reduce gastrotoxicity, but it may impact its bioavailability and efficacy. The acidic nature of aspirin can lead to passive diffusion and trapping in the gastric mucosal cell, causing gastrotoxicity. Additionally, aspirin inhibits the gastroprotective effects of PGE2 and PGI2 by inhibiting COX-1 in the stomach. Gastrointestinal complications, such as ulcers and bleeding, are more likely when taking higher or lower than 100 mg of aspirin daily [27, 28, 29, 30].

To minimize gastrotoxicity while enhancing bioavailability, various methods of administering aspirin have been suggested. These include using a diluted acetylsalicylate solution, an intravenous injection solution, a quickly dissolving tablet, a solution with added antacid, a fine-grained, highly buffered aspirin tablet, an enteric-coated tablet, or an aspirin substitute like acetaminophen [31, 32].

2.4 Reye syndrome

Reye syndrome is a rare and potentially fatal pediatric disease characterized by acute non-inflammatory encephalopathy with fatty liver failure. Epidemiological studies have shown a connection between Reye syndrome and the consumption of aspirin during or after a viral infection. Aspirin’s damage to cellular mitochondria may inhibit fatty-acid metabolism, leading to hepatic mitochondrial failure and high ammonia levels, which contribute to the neurologic symptoms of Reye syndrome. Reye syndrome cases significantly decreased after public cautions were issued against administering aspirin to children in the 1980s [33, 34, 35].

2.5 Aspirin withdrawal syndromes

Abruptly stopping aspirin, like many other medications, can lead to withdrawal syndromes, and in some cases, it can be fatal. The discontinuation of aspirin may transiently increase the risk of thrombotic events. Research has shown that aspirin withdrawal can cause a prothrombotic state in both clinical and animal studies. Some studies suggest that patients with known coronary disease may face a higher risk of new coronary events if they stop taking aspirin. Hence, it is crucial to identify at-risk individuals and inform them about the risks associated with aspirin discontinuation [36, 37, 38].

3. Unraveling Aspirin’s expanded applications

3.1 Aspirin in myocardial infarction

Cardiovascular disease, mainly caused by severe atherosclerosis, often leads to myocardial infarction due to thrombotic blockage of major coronary arteries. The primary cause of thrombus formation is the rupture of atherosclerotic plaques [39]. Aspirin is the preferred drug for long-term prevention of secondary myocardial infarction and stroke.

Current guidelines recommend a daily dose of 75 mg according to the ESC Guidelines, while other recommendations range between 100 and 150 mg. The use of aspirin for secondary prevention lowers the risk of new vascular events by about 20–25% overall [40, 41].

For males aged 45 to 70, aspirin is recommended for preventive measures if the potential benefit of reducing the risk of myocardial infarction outweighs the potential risk of bleeding (gastrointestinal or cerebral hemorrhage). Similarly, women aged 55 to 79 are advised to take aspirin for prophylaxis if the risk of ischemic stroke is reduced more than the potential risk of bleeding. In the US guidelines, the prescription for long-term cardiovascular protection ranges from 75 to 325 mg/day and tends to decrease over time [42].

Antiplatelet agents, particularly aspirin, play a crucial role in treating acute coronary syndromes by preventing existing thrombi from growing and new ones from forming. One significant trial, the ISIS-2 trial, highlighted the clinical significance of aspirin in acute myocardial infarction, both as monotherapy and in combination with thrombolysis to reopen occluded coronary arteries [43].

3.2 Aspirin in cerebrovascular events (stroke)

Cerebral ischemia, caused by obstructions in cerebral circulation, leads to decreased cerebral blood flow [44]. This condition can manifest as transient ischemic attacks (TIAs) or reversible and irreversible disabling strokes. Studies have investigated the use of high-dose intravenous aspirin (500 mg) in reducing cerebral microemboli in patients with recent strokes of arterial origin [45].

Various aspirin dosages may be needed to inhibit platelet aggregation and thrombogenesis caused by different platelet activation triggers [46]. Clinical data on the outcomes of different aspirin dosages in stroke patients are not yet fully outlined. Two significant clinical trials, the Dutch TIA study and the UK TIA trial, showed no difference in outcomes between low doses (30 mg/day and 283 mg/day) and larger doses (300 mg versus 1200 mg daily), although the larger doses resulted in more hemorrhage [47, 48].

The US guidelines recommend 325 mg of oral aspirin within the first 24 to 48 hours following the onset of a stroke [49].

Aspirin’s importance in stroke patients is further highlighted by the recurrence of thrombotic cerebrovascular events after aspirin is removed, underscoring the significance of aspirin-induced platelet activity restriction for clinical prognosis [50, 51, 52, 53].

3.3 Aspirin in peripheral arterial occlusive disease (PAD)

Peripheral arterial occlusive disease (PAD) is characterized by peripheral artery stenosis and occlusion, with the lower limbs being most commonly affected [54, 55].

Aspirin has been extensively studied as an antiplatelet medication for PAD. However, aspirin-resistant platelets are common in PAD patients [56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66].

For all PAD patients, it is recommended to evaluate other authorized antiplatelet medications and consider combining aspirin with medications to lower blood pressure and cholesterol, as well as encouraging smoking cessation for optimal clinical impact [67].

3.4 Aspirin in venous thromboembolism (VTE)

Venous thromboembolism (VTE) is a serious and potentially fatal side effect of acute surgical procedures, usually presenting as deep vein thrombosis (DVT) with pulmonary embolism (PE) as the main complication [68].

Aspirin influences various targets to alter the production of venous thrombus, primarily by preventing the synthesis of thromboxane and reducing thrombin production, thus reducing platelet aggregation at antiplatelet dosages [69, 70, 71].

Studies like the “Warfarin and Acetylsalicylic Acid” (WARFASA) research and the “Aspirin to Prevent Recurrent Venous Thromboembolism” (ASPIRE) study have explored whether low-dose aspirin can be effective in preventing VTE after guideline-directed anticoagulation [72, 73].

3.5 Preeclampsia

Preeclampsia is a major risk factor for preterm birth and a leading cause of maternal and fetal mortality. It is characterized by hypertension, proteinuria, and a severe maternal systemic inflammatory response [74, 75]. Insufficient production of prostacyclin (PGI2) during early gestation is linked to the pathophysiology of pregnancy-induced hypertension (PIH). Aspirin, due to its anti-inflammatory and anticoagulant properties, is suggested as a possible effective treatment option for Preeclampsia [76, 77, 78, 79, 80, 81, 82, 83]. Aspirin’s ability to cross the placenta and work at 50–150 mg makes it a useful therapy, but >75 mg/day is better [84].

The American College of Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine recommend starting low-dose aspirin (81 mg/day) between 12 and 28 weeks of pregnancy for PE prevention, continuing daily until delivery for women at high risk of PE. Low-dose aspirin during early pregnancy is generally safe for the fetus and newborn [85, 86].

Aspirin appears safe for preterm prelabour membrane rupture. Its efficacy in reducing preterm rupture risk is uncertain [87]. Finding a safe and effective dose for women with medical conditions remains a priority, as certain disorders may reduce aspirin’s effectiveness [88, 89].

3.6 Cancer prevention

Inflammation plays a role in various diseases, including cancer. ASA shows promise as a chemo-preventive drug against colorectal, breast, lung, stomach, ovarian, hepatic, and prostate cancers. ASA’s mechanisms involve inhibiting COX-2, elevating arachidonic acid, and influencing sphingosine pathways. Low doses of ASA are effective in breast and colon cancer prevention. ASA’s impact on Wnt/b-catenin pathway and NF-B activation further supports its anti-cancer potential. Regular aspirin use is associated with lower colorectal cancer incidence and mortality rates. It may also benefit patients with breast and prostate cancer. Daily antiplatelet doses of 75–100 mg appear effective in preventing tumor recurrence and suppressing metastases. However, aspirin’s role in primary cancer prevention and individual tumor response requires further investigation, considering both benefits and risks [16, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110].

3.7 Neurological disorders

Neuropsychiatric disorders, including Alzheimer’s disease, affect the central nervous system and are characterized by protein buildup and synaptic dysfunction [111]. The pathogenesis involves neuroinflammation and mitochondrial dysfunction [112, 113]. β-amyloid leads to mitochondrial dysfunction and inflammation, making neurons more susceptible to ischemia responses [113]. Prolonged neuroinflammation may contribute to β-amyloid accumulation in plaques, and platelets are a significant source of β-amyloid, suggesting APP as an Alzheimer’s biomarker [114, 115, 116, 117]. Cognitive deficits in Alzheimer’s patients are related to β-amyloid oligomers in the CNS [118]. Aspirin has shown potential in reducing amyloid aggregates and inflammation [119, 120, 121]. However, existing therapies have not yielded definitive results due to the complexity of the disease [122, 123]. Aspirin’s anti-thrombotic properties may help prevent cognitive decline caused by ischemia and it could target apolipoprotein E isoforms and inflammatory substances [124]. Epidemiological trials suggest that NSAIDs, including aspirin, when taken early and consistently for two or more years, may lower the prevalence of Alzheimer’s. Nevertheless, to confirm these findings, more comprehensive, large-scale, prospective randomized studies considering genetic variants and risk factors are needed. Presently, there are no substantial prospective trials on aspirin for Alzheimer’s prevention or treatment [125].

3.8 Role of aspirin in COVID-19

COVID-19 is associated with an increased risk of thrombosis, and aspirin has been shown to reduce platelet activation in COVID-19 patients. Anticoagulation and aspirin have been recommended for severe COVID-19 patients [126, 127, 128, 129, 130, 131]. Anticoagulant treatment reduced mortality in severe COVID-19 patients [132]. Aspirin decreased platelet activation in COVID-19 patients, while studies showed increased platelet reactivity inhibited by high-dose aspirin in vitro [133, 134, 135, 136]. Autopsies revealed high rates of thromboembolic incidents, highlighting COVID-19-induced coagulopathy and the need for further research on potential therapeutic approaches [137]. Aspirin may have potential antiviral effects, but more research is needed in this area [138, 139, 140].

3.9 Effect of aspirin in renal disease

Limited research exists on low-dose aspirin regimens (75 to 325 mg/d). A recent finding indicates that 75 mg of aspirin reduces uric acid and creatinine excretion in older patients [141, 142]. In most cases, except for patients with renal insufficiency, cirrhosis, or heart failure, aspirin does not affect renal function when taken in anti-inflammatory doses [143, 144, 145].

3.10 Impact of aspirin in stem cell therapy

Aspirin has been found to have positive effects on various stem cell functions and therapies. In preclinical studies, aspirin has been shown to enhance the functions of different stem cell types. For example, it promotes the functions of osteogenic, tenogenic, and cardiomyocyte stem cells. Co-treatment of aspirin with stem cells has also been found to enhance their immunomodulatory capabilities [146].

Studies have shown that aspirin exposure affects stem cell behavior in both in vitro and in vivo environments. The duration and dosage of aspirin exposure determine the extent to which it influences stem cell growth and functions. For instance, aspirin has been shown to induce the death of mesenchymal stem cells via the Wnt/catenin pathway [147].

In treating bone abnormalities, aspirin treatment has been found to improve bone repair caused by bone marrow mesenchymal stem cells [148]. In other studies, aspirin has been demonstrated to enhance the osteogenic potential of human dental pulp stem cells and human mesenchymal stem cells [149, 150].

3.11 Kawasaki’s disease

Kawasaki’s disease is a pediatric vasculitis characterized by various clinical manifestations, such as high fever, rashes, and cervical lymphadenopathy. Aspirin has been used in the treatment of Kawasaki’s disease, typically in conjunction with intravenous immunoglobulin (IVIG). During the acute stage of the disease, high-dose aspirin is administered at anti-inflammatory levels (80 to 100 mg/kg per day) along with IVIG [151, 152].

The use of aspirin during the acute stage of Kawasaki’s disease has been found to reduce fever duration and lower hemoglobin levels [153]. Following the acute phase, low-dose aspirin is continued for six to eight weeks to reduce the risk of coronary artery aneurysms [154]. A meta-analysis on the effectiveness of aspirin in Kawasaki’s disease revealed that the risk of coronary artery aneurysms is reduced by 9% and 4% when high-dose aspirin is administered along with IVIG within 30 and 60 days of disease onset, respectively [155].

4. Genetic influence on aspirin response: exploring through pharmacogenetics and pharmacogenomics

Pharmacogenetics, the study of how genetic variations influence drug responses, has emerged as a groundbreaking field in medicine. It provides valuable insights into individual variations in drug metabolism, efficacy, and safety, offering the promise of personalized therapies. Aspirin, a widely used medication known for its antiplatelet effects in cardiovascular disease prevention, is one such drug whose efficacy can be influenced by genetic factors. This article explores the role of pharmacogenetics in understanding genetic variants affecting aspirin response, with a focus on the impact of COX-1 gene polymorphisms, drug metabolizing enzyme variants (e.g., CYP2C19), and genetic variability in platelet receptors and pathways.

4.1 COX-1 gene polymorphisms and aspirin resistance

The COX-1 gene contains the genetic instructions needed to produce an enzyme called cyclooxygenase-1. This enzyme plays a critical role in the creation of molecules called prostaglandins. Prostaglandins are involved in various physiological processes, including promoting inflammation, contributing to pain signaling, and participating in the formation of blood clots. Aspirin functions by irreversibly inhibiting COX-1, preventing its normal activity. This inhibition leads to a decrease in the production of prostaglandins, which in turn reduces inflammation and pain, as well as lowers the likelihood of blood clot formation.

Despite aspirin’s effectiveness, some individuals might not experience the anticipated results from its use. This condition is known as aspirin resistance. In cases of aspirin resistance, the expected outcomes, such as reduced blood clot formation, might not be achieved as effectively.

Aspirin resistance can be attributed to genetic variations within the COX-1 gene. These genetic differences can result in alterations in the structure and function of the COX-1 enzyme. One well-known genetic alteration is called the A-842G polymorphism, also referred to as C50T or rs3842787 SNP. This particular genetic variant has gained recognition due to its association with a diminished suppression of COX-1 activity by aspirin. Consequently, the ability of aspirin to prevent platelet aggregation, a key step in clot formation, is compromised in individuals carrying this genetic variant.

The implications of possessing the A-842G polymorphism are notable. Individuals with this genetic variation might face an increased risk of cardiovascular incidents, even when undergoing aspirin therapy. This elevated risk is attributed to the reduced effectiveness of aspirin in preventing platelet aggregation, which can contribute to the formation of blood clots and subsequent cardiovascular events [156].

4.2 Genetic variability in CYP2C19 enzyme and its impact on aspirin metabolism

Aspirin is transformed within the liver through a series of biochemical processes, involving various enzymes responsible for breaking down the drug. Among these enzymes, the cytochrome P450 (CYP) enzymes play a primary role. However, genetic differences in these enzymes can have a significant impact on how aspirin is processed, which can result in varying levels of its effectiveness and safety.

An essential enzyme in the metabolism of aspirin is known as CYP2C19. This enzyme is responsible for converting aspirin into its active form through a chemical reaction. However, genetic variations, or polymorphisms, occurring within the CYP2C19 gene can lead to reduced activity of this enzyme. This reduction in enzyme activity directly affects the speed and efficiency with which aspirin is converted into its active form.

Individuals who carry genetic variants that result in poor CYP2C19 metabolism might experience a diminished response to aspirin treatment. Essentially, their bodies might not process aspirin as effectively, which could lead to a weaker impact in terms of its intended effects.

The consequences of this genetic variability can be clinically significant, particularly in the context of cardiovascular health. Reduced responsiveness to aspirin therapy due to poor CYP2C19 metabolizer status has been associated with an increased risk of experiencing negative cardiovascular events. In simpler terms, individuals with certain genetic variants might not receive the expected benefits from aspirin, and this could potentially lead to more adverse outcomes related to heart health [157].

4.3 P2Y12 receptor gene variation and aspirin response

Aspirin exerts its ability to prevent blood clot formation primarily by inhibiting an enzyme called COX-1. However, beyond this mechanism, there are genetic factors that influence the way platelet receptors and pathways respond to aspirin’s effects.

One such example involves a genetic variation known as rs5918, found within the gene responsible for producing the P2Y12 receptor. The P2Y12 receptor plays a significant role in the activation and aggregation of platelets, which are essential steps in the clotting process. Depending on an individual’s genetic makeup, specifically the alleles they carry for this variation, such as the C34T allele, their response to aspirin can be affected. Studies have revealed that individuals with certain variants of rs5918 might experience reduced platelet inhibition when exposed to aspirin. This diminished response can potentially weaken aspirin’s effectiveness in preventing the formation of blood clots.

Moreover, genetic variability in other platelet pathways also plays a role in influencing how aspirin’s effects are modulated. For instance, pathways involving the glycoprotein IIb/IIIa receptor, another crucial player in platelet activation, can be influenced by genetic differences. These variations can lead to differences in how aspirin interacts with these receptors and pathways, potentially impacting its ability to inhibit platelet aggregation effectively [158].

In essence, while aspirin’s primary action is mediated through COX-1 inhibition, genetic factors related to platelet receptors and pathways contribute to the overall response to aspirin therapy. Variations in genes like rs5918 and pathways involving receptors like glycoprotein IIb/IIIa can impact an individual’s platelet response to aspirin. This underscores the complexity of how genetics can influence drug interactions and responses, and highlights the importance of considering genetic factors when tailoring treatment plans for optimal patient outcomes.

4.4 Impact of SLCO1B1 gene variants on aspirin absorption and metabolism

The SLCO1B1 gene is a crucial player in the absorption and metabolism of various drugs, including aspirin, by encoding a protein responsible for transporting these substances into liver cells. This gene is a member of the organic anion transporting polypeptide (OATP) family, which facilitates the uptake of a wide range of compounds into hepatocytes (liver cells). Variants or mutations in the SLCO1B1 gene can influence its functionality, leading to alterations in drug absorption, distribution, metabolism, and excretion (ADME) processes.

The liver plays a central role in drug metabolism, as it processes drugs to make them more water-soluble and easier to eliminate from the body. The SLCO1B1 protein contributes to this process by transporting drugs and their metabolites from the bloodstream into the liver cells, where they can undergo further metabolic transformations.

Several studies have investigated the impact of SLCO1B1 gene variants on drug response and adverse reactions. One well-studied example is the influence of SLCO1B1 variants on statin medications, which are commonly prescribed to lower cholesterol levels. Some specific SLCO1B1 variants have been associated with decreased transport of certain statins into the liver cells, resulting in higher systemic drug concentrations. This can increase the risk of side effects, particularly muscle-related adverse events.

In the context of aspirin, variations in the SLCO1B1 gene may affect the liver’s ability to absorb and metabolize the drug. Aspirin is a widely used nonsteroidal anti-inflammatory drug (NSAID) that also has antiplatelet effects, making it valuable for preventing cardiovascular events. However, genetic differences in drug metabolism can lead to variability in aspirin’s efficacy and safety.

The concept of pharmacogenetics explores how individual genetic makeup influences responses to drugs. Understanding the impact of specific genetic variants on drug handling can help tailor medication regimens for patients, optimizing therapeutic outcomes while minimizing adverse effects. In the case of SLCO1B1 gene variants, genetic testing could offer insights into an individual’s ability to metabolize and respond to drugs like aspirin.

It’s important to note that while the SLCO1B1 gene’s significance in drug transport and metabolism is well-established, individual responses to drugs are influenced by a complex interplay of genetic, environmental, and physiological factors. Genetic testing and personalized medicine are rapidly evolving fields that aim to provide more precise and effective treatment strategies [159, 160, 161, 162].

4.5 Genetic variations in ABCB1 gene and Aspirin’s antiplatelet effects

The ABCB1 gene, also known as the multidrug resistance 1 (MDR1) gene, encodes a protein called P-glycoprotein (P-gp) that functions as an efflux transporter. P-gp is widely expressed in various tissues, including the intestines, liver, and blood-brain barrier. Its primary role is to transport a diverse range of substances, including drugs, toxins, and metabolites, out of cells. In the context of drug therapy, P-gp plays a crucial role in regulating the absorption and distribution of drugs, thereby affecting their bioavailability and efficacy.

The transport activity of P-gp is particularly important in cells that line blood vessels and in organs like the kidneys. In blood vessel lining cells, P-gp helps in transporting drugs from these cells back into the bloodstream, limiting their accumulation within the cells. This mechanism can affect the overall distribution and clearance of drugs, influencing their therapeutic effects and potential side effects.

Aspirin, an NSAID with anti-inflammatory and antiplatelet effects, is one of the drugs influenced by genetic variations in the ABCB1 gene. Aspirin is widely used for its antiplatelet properties, which help prevent blood clot formation and reduce the risk of cardiovascular events. The ability of aspirin to exit cells, including platelets, is influenced by P-gp-mediated transport. Genetic differences in the ABCB1 gene can lead to variations in P-gp activity, which in turn affects aspirin’s movement out of cells and its overall antiplatelet effects.

Several studies have explored the impact of ABCB1 gene variants on drug responses and clinical outcomes. Variations in the ABCB1 gene have been associated with altered drug pharmacokinetics, efficacy, and safety profiles. For example, individuals with certain ABCB1 gene variants might have reduced P-gp activity, leading to altered drug distribution and potential differences in treatment response [163, 164, 165, 166, 167].

4.6 Role of genetic polymorphisms in ITGA2 gene and Aspirin response

The ITGA2 gene encodes a protein known as integrin alpha-2 (α2), which is a platelet receptor involved in the process of platelet aggregation and blood clotting. Integrins are cell adhesion molecules that play a key role in linking cells to the extracellular matrix and other cells, and they are particularly important for platelet function. Platelets are crucial components of blood that play a pivotal role in forming blood clots to prevent excessive bleeding.

The integrin alpha-2β1 receptor, formed by the combination of integrin alpha-2 and beta-1 subunits, is present on the surface of platelets. It facilitates platelet adhesion to collagen, a component of the extracellular matrix, and is essential for the initial stages of blood clot formation at sites of vascular injury. This adhesion is a critical step in platelet aggregation, which leads to the formation of a stable blood clot that prevents further bleeding.

The effectiveness of aspirin in preventing platelet aggregation and reducing the risk of blood clots may be influenced by genetic variations in the ITGA2 gene. Genetic polymorphisms in this gene could potentially impact the structure and function of the integrin alpha-2 receptor, affecting its ability to interact with collagen and initiate platelet aggregation. Aspirin, a well-known antiplatelet agent, works by inhibiting the production of certain molecules that promote platelet aggregation, thereby reducing the risk of clot formation.

Research has shown that genetic variations in platelet receptors like integrins can influence the responsiveness of platelets to antiplatelet agents, including aspirin. These variations might lead to differences in platelet aggregation, clot formation, and response to aspirin therapy. Therefore, understanding the role of genetic polymorphisms in the ITGA2 gene and their impact on platelet function could provide valuable insights into individual variability in aspirin’s antiplatelet effects [168, 169, 170, 171, 172].

4.7 Potential influence of PGF and TXB2 gene variations on Aspirin’s antiplatelet effects

Genetic variations in the genes responsible for the synthesis of prostaglandins (PGF) and thromboxanes (TXB2) can have a significant impact on how aspirin functions as an anti-inflammatory and antiplatelet agent. Aspirin’s mechanism of action involves inhibiting the production of prostaglandins and thromboxanes, which are important signaling molecules involved in various physiological processes, including inflammation and platelet aggregation.

Prostaglandins and thromboxanes are derived from arachidonic acid, a fatty acid found in cell membranes. These molecules play critical roles in regulating inflammation, blood vessel dilation and constriction, and platelet activation. Prostaglandins are involved in mediating pain, fever, and inflammation, while thromboxanes contribute to platelet aggregation and blood clot formation.

Aspirin exerts its effects by irreversibly inhibiting the enzyme cyclooxygenase (COX), particularly COX-1 and COX-2. COX enzymes are responsible for converting arachidonic acid into prostaglandins and thromboxanes. By inhibiting COX, aspirin reduces the production of these molecules, which leads to decreased inflammation and inhibited platelet aggregation.

Genetic variations in the genes encoding key enzymes involved in prostaglandin and thromboxane synthesis can influence how aspirin affects these processes. Variants in these genes may lead to altered enzyme activity, resulting in variations in the levels of prostaglandins and thromboxanes even in the presence of aspirin.

Aspirin’s anti-inflammatory and antiplatelet effects are crucial for its therapeutic benefits, such as reducing the risk of cardiovascular events. Genetic differences in the PGF and TXB2 genes could potentially impact aspirin’s efficacy in suppressing inflammation and platelet activation. This could translate to variability in aspirin’s ability to prevent blood clot formation and reduce the risk of adverse cardiovascular events.

Pharmacogenetic studies in this area aim to elucidate the relationship between genetic variations and aspirin response. By identifying genetic markers associated with altered aspirin metabolism or activity, healthcare providers can potentially tailor aspirin dosages or recommend alternative treatments to optimize therapeutic outcomes while minimizing risks [173].

4.8 CYP2C9 gene variations as a key factor in aspirin response and bleeding risk

The CYP2C9 gene encodes an enzyme responsible for metabolizing various drugs, including aspirin. Genetic variations within the CYP2C9 gene can impact the rate at which this enzyme metabolizes aspirin, leading to variability in drug metabolism and response. One significant aspect influenced by these genetic differences is the risk of bleeding due to altered aspirin metabolism.

Specific variants of the CYP2C9 gene are associated with reduced enzyme activity, resulting in slower metabolization of aspirin. Consequently, individuals carrying these variants may experience higher levels of aspirin in their bloodstream after taking a standard dose. This elevated drug concentration can potentiate aspirin’s antiplatelet effects, increasing the risk of bleeding events. Patients with such genetic variants might be more susceptible to bleeding complications, especially in situations requiring surgery or other interventions.

To mitigate the bleeding risk while maintaining aspirin’s therapeutic benefits, personalized dosing strategies can be employed. Lower aspirin doses might be necessary for individuals with reduced CYP2C9 enzyme activity. By aligning the dosage with an individual’s genetic makeup, healthcare providers can balance the antiplatelet effects of aspirin with the potential bleeding risk, offering a safer and more effective treatment approach [174, 175].

4.9 GPIa polymorphism and aspirin response

The GPIa C807T polymorphism has been the subject of investigation in various studies focusing on both surrogate and clinical outcomes, particularly in patients with coronary artery disease (CAD) who are undergoing aspirin therapy. However, the collective findings from these studies have consistently indicated that the GPIa C807T polymorphism does not significantly contribute to the variability observed in the response to aspirin.

Multiple investigations into surrogate and clinical endpoints have consistently failed to establish a substantial role for the GPIa C807T polymorphism in accounting for the variability in aspirin response among CAD patients. Despite its potential involvement in platelet function and thrombotic processes, this specific genetic variation does not seem to play a significant role in influencing the efficacy of aspirin treatment in these individuals.

In contrast, other genetic factors have been explored in relation to aspirin response. The GPIba C-5 T polymorphism, another genetic variation associated with platelet function, has shown potential significance. Studies have suggested that GPIba C-5 T might contribute to the development of aspirin resistance in patients. This implies that individuals carrying this particular genetic variant may be more likely to exhibit reduced responsiveness to aspirin’s antiplatelet effects, which could impact the therapeutic benefits of the treatment.

Furthermore, investigations have also extended to other genetic markers, such as GPIaa C807T and COX-2G-765C. These studies aimed to understand their roles in influencing the response of patients undergoing aspirin therapy. The results have indicated that while GPIaa C807T does not appear to be a significant determinant of aspirin responsiveness, the COX-2G-765C variant also does not appear to significantly contribute to the response variability of patients on aspirin therapy [176].

4.10 Impact of GPIIIa polymorphism on aspirin response

The platelet glycoprotein IIIa (GPIIIa) is a component of the GPIIb/IIIa complex, serving as the receptor for fibrinogen and other adhesive molecules. Encoded by the ITGB3 gene, GPIIIa plays a critical role in platelet aggregation. A diallelic polymorphism of the ITGB3 gene, known as the PlA1/A2 polymorphism, affects platelet function. This polymorphism involves a single transition at position 1565 in exon 2 of the gene, resulting in two allelic variants: P1A1 and P1A2.

The GPIIb/IIIa complex, formed by the combination of GPIIb and GPIIIa, is essential for platelet aggregation, an integral step in forming blood clots. Fibrinogen and other adhesive molecules bind to this complex, promoting platelet aggregation at sites of vascular injury. The PlA1/A2 polymorphism influences the structure and function of GPIIIa, potentially impacting platelet aggregation and overall thrombotic processes.

Among individuals of white ethnicity, about 25% express the P1A2 allele, characterized by a Leu 33 Pro substitution. The P1A2 allele has been implicated as a potential risk factor for coronary artery disease (CAD) in some studies, though this association has not been universally confirmed.

In the context of aspirin therapy and CAD, conflicting results have emerged from studies. Research involving patients with stable CAD who received aspirin doses ranging from 80 to 325 mg/day revealed contradictory findings regarding the impact of the PlA1/A2 genotype. Some studies reported an association between the PlA1/A1 genotype and a twofold increased risk of high platelet reactivity, as assessed using the Platelet Function Analyzer-100 (PFA-100).

These results suggest that the PlA1/A2 polymorphism of the ITGB3 gene can influence platelet reactivity and potentially contribute to the variability in aspirin response observed in patients with CAD. The conflicting outcomes underscore the complexity of genetic influences on platelet function and aspirin’s antiplatelet effects. The PlA1/A2 polymorphism’s role in cardiovascular risk and aspirin responsiveness necessitates further research to fully elucidate its impact and potential clinical implications [177, 178].

5. Clinical implications of genetic testing for aspirin therapy

5.1 Personalized aspirin therapy

Pharmacogenetic testing has emerged as a promising approach to optimizing medical treatments by taking an individual’s genetic makeup into account. This tailored approach involves analyzing a patient’s genetic information to pinpoint specific genetic variations that might influence their response to medications, including aspirin. By gaining a deeper understanding of a person’s genetic profile, healthcare professionals can finely adjust aspirin therapy to maximize its efficacy while minimizing potential adverse effects.

One of the key applications of pharmacogenetic testing in the context of aspirin therapy revolves around personalized dosing. Genetic variations in crucial drug-metabolizing enzymes, such as cytochrome P450 2C19 (CYP2C19), can substantially impact the way the body processes aspirin. Notably, patients harboring certain genetic variants might necessitate either higher or lower doses of aspirin to achieve the intended antiplatelet effect [179]. This adaptation in dosage takes into consideration an individual’s genetic predisposition for metabolizing the drug, thereby aiming to optimize aspirin’s impact on platelet aggregation.

Pharmacogenetic testing also offers a means of identifying individuals who might be predisposed to certain challenges during aspirin therapy. For instance, specific genetic variants within platelet receptors or polymorphisms within the COX-1 gene, responsible for cyclooxygenase-1 production, could lead to reduced responsiveness to aspirin or an elevated susceptibility to adverse reactions. By identifying these individuals through genetic testing, healthcare providers can proactively tailor treatment plans. This might involve considering alternative medications or modifying dosages to ensure an optimal response while minimizing risks [180, 181].

5.2 Reducing adverse events

Aspirin is generally regarded as a safe and well-tolerated medication, but it’s important to recognize that certain individuals might encounter adverse events, such as gastrointestinal bleeding or hypersensitivity reactions. In this context, pharmacogenetic testing emerges as a valuable tool for identifying patients who could be at an elevated risk of experiencing such adverse events, thereby informing appropriate clinical decisions.

One notable application of pharmacogenetic testing is in identifying patients who might be more susceptible to aspirin-related gastrointestinal bleeding. Individuals harboring specific genetic variants within drug-metabolizing enzymes might have an increased predisposition to this adverse effect. By utilizing genetic profiling to identify these patients, healthcare providers gain the ability to implement preventive measures or explore alternative medication options to minimize the risk of gastrointestinal bleeding [182]. This tailored approach is particularly advantageous in ensuring patient safety while optimizing the therapeutic benefits of aspirin.

Moreover, genetic testing can play a crucial role in identifying individuals at a higher risk of hypersensitivity reactions to aspirin, such as those with aspirin-exacerbated respiratory disease (AERD). By recognizing these patients through genetic analysis, healthcare providers can avoid prescribing aspirin to them. This proactive measure helps prevent potentially severe allergic reactions and enables healthcare professionals to explore alternative treatment strategies that will not trigger adverse reactions [183].

5.3 Improving cardiovascular outcomes

Cardiovascular diseases (CVDs), including heart attacks and strokes, are significant health concerns on a global scale. Among the interventions for managing these conditions, aspirin emerges as a crucial player in the secondary prevention of CVDs. By reducing the risk of recurring cardiovascular events, aspirin has established its importance. However, it’s important to recognize that aspirin’s effectiveness might exhibit variability influenced by an individual’s unique genetic composition.

Pharmacogenomic insights, obtained through genetic testing, offer a pathway to identifying individuals who are more likely to derive substantial benefits from aspirin therapy in the context of cardiovascular event prevention. Genetic testing provides healthcare professionals with valuable information that helps them recognize patients who could experience enhanced advantages from aspirin treatment. For instance, patients harboring specific genetic variants linked to heightened platelet aggregation or increased inflammation might experience more pronounced benefits from aspirin therapy. This knowledge empowers healthcare providers to offer a targeted approach to these patients, tailoring their treatment to optimize outcomes.

Conversely, genetic variations can also lead to reduced responsiveness to aspirin, a phenomenon known as aspirin resistance. Identifying individuals who possess these genetic variants is pivotal in guiding clinical decisions. Healthcare providers armed with this genetic information can consider alternative treatment strategies for patients who might not respond optimally to aspirin. This proactive approach ensures that patients receive the most suitable therapies to achieve the best possible health outcomes [184].

6. Conclusion

Aspirin, a widely used medication dating back to 1904, holds a prominent place in the medical world. Originally known for its pain-relieving, anti-inflammatory, and fever-reducing properties, its applications have expanded over the years, particularly in secondary prevention for cardiovascular disease. Additionally, its anti-inflammatory attributes have led to exploration in preventing inflammation-related cancers like colon cancer. With its low cost and extensive clinical experience, aspirin is now being investigated in various fields, including neurological diseases, virus-associated conditions, and bone physiology.

Despite its widespread use, the evaluation of aspirin’s benefits and potential harms is essential, as it may lead to severe bleeding or damage to the stomach mucosa. To unlock its full potential, ongoing research on the molecular mechanisms of aspirin’s action is uncovering predictive biomarkers. This newfound understanding allows for targeted, safer, and more effective use of this simple yet powerful medication.

In the realm of personalized medicine, the integration of pharmacogenetic and pharmacogenomic information into aspirin therapy represents a significant advancement. By tailoring aspirin treatment based on an individual’s genetic profile, precise dosing can be achieved, resulting in improved treatment outcomes and better management of aspirin-related challenges. As personalized medicine continues to progress, its application holds great promise for shaping the future of aspirin therapy, benefitting patients in cardiovascular disease management and other areas.

To fully realize these advancements, collaborative efforts between researchers, clinicians, and policymakers are vital. By working together, these findings can be translated into routine clinical practice, ultimately optimizing aspirin’s therapeutic benefits and enhancing patient care in a wide range of medical scenarios.

Acknowledgments

The authors express their sincere thanks to the Faculty of Pharmacy, Integral University, Lucknow for encouraging and providing research atmosphere.

Conflict of interest

The authors declare no conflict of interest.