アメリカ国立衛生研究所（NIH）が推進する「Precision Medicine Initiative」では、遺伝子情報、環境要因、ライフスタイルデータを統合し、個別化医療を実現する取り組みが進められています。今後、日本でも同様のプロジェクトが拡大し、遺伝子検査を活用した治療法の選択が一般化する可能性があります。
Cardiovascular disease is one of the leading causes of death worldwide, and its prevention and treatment are important challenges in the medical field. Aspirin is widely used to prevent cardiovascular events due to its antiplatelet effect. However, recent studies suggest that the effect of aspirin may be influenced by an individual’s genetic background. In this article, we evaluate aspirin responsiveness through genetic testing and explore how it can be applied to heart disease prevention. Japan Heart Foundation+1J-STAGE+1
The role and limitations of aspirin
Aspirin inhibits the cyclooxygenase-1 (COX-1) enzyme in platelets, suppressing the production of thromboxane A2 and preventing platelet aggregation. This inhibits the rupture of arteriosclerotic plaques and the formation of blood clots, contributing to the prevention of myocardial infarction and stroke. However, some patients have been reported to develop “aspirin resistance,” in which the effects of aspirin are not fully achieved. This resistance is thought to be caused by individual differences in pharmacokinetics, drug interactions, and genetic factors. Japan Heart Foundation
Genetic polymorphisms and aspirin response
Genetic polymorphisms, or individual differences in the base sequence of genes, are known to affect the efficacy and side effects of drugs. The following genetic polymorphisms are related to aspirin responsiveness: Japan Heart Foundation+1J-STAGE+1
1. COX-1 (PTGS1) gene
Polymorphisms in the PTGS1 gene, which codes for the COX-1 enzyme, may directly affect the inhibitory effect of aspirin. It has been suggested that in patients with certain polymorphisms, aspirin inhibits COX-1 insufficiently, resulting in failure to suppress platelet aggregation. Japan Heart Foundation
2. GPIIb/IIIa (ITGB3) gene
Polymorphisms in the ITGB3 gene, which encodes the GPIIb/IIIa receptor, an integrin on the platelet membrane, are also associated with aspirin responsiveness. If you have certain polymorphisms, platelet aggregation may increase, weakening the effectiveness of aspirin. Cancer Information Network +5 Japan Heart Foundation +5 J-STAGE +5
3. PEAR1 gene
Polymorphisms in the PEAR1 gene, which is involved in platelet activation, have been reported to be associated with an increased risk of cardiovascular events during aspirin treatment. In patients with these polymorphisms, the preventive effect of aspirin may be reduced.
Clinical Applications of Genetic Testing
Genetic testing to detect these gene polymorphisms may be useful for individualizing aspirin treatment. Specific applications include the following:
1. Prediction of treatment outcomes
Genetic testing could identify patients at high risk for aspirin resistance and allow consideration of alternative antiplatelet drugs and treatment strategies.
2. Risk assessment of side effects
Long-term use of aspirin carries the risk of side effects such as gastrointestinal bleeding. Through genetic testing, patients at high risk for these conditions can be identified and preventive measures can be implemented。ダイヤモンド+6odori-clinic.com+6amed.go.jp+6
3. Promoting personalized medicine
By selecting the most appropriate treatment based on each patient’s genetic background, it is possible to maximize therapeutic efficacy and minimize side effects.
Research Cases
There are many studies on gene polymorphisms and aspirin responsiveness. For example, the National Cerebral and Cardiovascular Center has revealed that the effectiveness of the antiplatelet drug clopidogrel is affected by CYP2C19 gene polymorphisms. Using a similar approach, research is being conducted to examine the relationship between the effectiveness of aspirin and gene polymorphisms. Japan Heart Foundation+1J-STAGE+1
Furthermore, it has been shown that the effectiveness of aspirin is affected by mutations in the PI3K pathway. Specifically, it has been reported that taking aspirin may reduce the risk of cancer recurrence in colorectal cancer patients with mutations in the PIK3CA gene. カーネット+1ダイヤモンド+1ダイヤモンド+1カーネット+1
Limitations and challenges of genetic testing
1. Gene-environment interactions
Although genetic polymorphisms do affect aspirin responsiveness, the effectiveness of the drug is not determined by a single genetic variant alone. For example, environmental factors such as diet, exercise habits, smoking, alcohol consumption, and concomitant medications also play an important role. Further research is needed to accurately assess the extent to which these factors affect the effectiveness of aspirin.
2. Cost-effectiveness issues
Currently, genetic testing is relatively expensive and routinely performing it on all patients may be economically difficult. In particular, aspirin is generally low-cost and widely available, the cost-effectiveness of performing genetic testing may be questioned. It is important to establish criteria for which patients should undergo genetic testing.
3. Preparation of clinical guidelines
Currently, many countries and medical institutions have standard guidelines for the administration of aspirin, but guidelines for personalized medicine that incorporate genetic testing are still in development. More clinical trials are required to create guidelines based on reliable data.
4. Ethical and legal issues
When using genetic testing, how individual genetic information is managed is an important issue. It is necessary to strike a balance between ensuring patient privacy and using data to improve the quality of medical care. In addition, legal provisions regarding how insurance companies and employers handle genetic information are also important.
Aspirin Alternatives and Personalized Medicine
If genetic testing reveals aspirin resistance, alternative treatment options are available. Below are some alternatives to aspirin and personalized medicine approaches.
1. Clopidogrel (Plavix)
Clopidogrel is an antiplatelet drug that prevents platelet aggregation by inhibiting the P2Y12 receptor. Although its metabolic efficiency varies depending on the CYP2C19 gene polymorphism, it is a promising alternative treatment option for aspirin-resistant patients.
2. Ticagrelor (Brilinta)
Ticagrelor is a reversible P2Y12 receptor inhibitor with stronger antiplatelet activity than clopidogrel. It is less susceptible to genetic polymorphisms and is considered effective in patients for whom aspirin is ineffective.
3. Warfarin and DOACs (direct oral anticoagulants)
For the prevention of blood clots, anticoagulants (warfarin, rivaroxaban, etc.) may be used instead of antiplatelet drugs. In particular, anticoagulants may be recommended over antiplatelet drugs in patients with atrial fibrillation.
Latest research using genetic testing
Research into the relationship between genetic testing and aspirin responsiveness is ongoing around the world. Below are some of the latest research findings.
1. Relationship between gene polymorphisms and aspirin effectiveness
A meta-analysis published in 2022 showed that aspirin has a reduced platelet inhibitory effect in patients with certain polymorphisms in the COX-1 (PTGS1) gene. The study also reported a high incidence of aspirin resistance, especially in Asian populations ( reference: PubMed ).
2. Attempts at individualized dosing of aspirin
A clinical trial published in 2023 showed that patients at high risk of aspirin resistance using genetic testing were given a combination of low-dose aspirin and clopidogrel, which significantly reduced the incidence of cardiovascular events. These research results suggest the effectiveness of personalized medicine using genetic testing.
3. Use of artificial intelligence (AI) and genetic data
By utilizing AI technology and integrating the analysis of genetic information and patient clinical data, more accurate prediction models of aspirin responsiveness are being developed. In particular, analysis using machine learning is making it possible to assess risk by combining multiple gene mutations and environmental factors, rather than just a single gene polymorphism.
Implementation in the medical field and future prospects
When introducing genetic testing into actual medical practice, the following points must be considered:
1. Establishing standardized testing protocols
Currently, genetic testing methods and analysis standards vary depending on the research institution, and standardization is required. If international guidelines are established, genetic testing may be used more widely.
2. Education and awareness of medical professionals
In order to correctly interpret genetic test results and link them to appropriate treatment, doctors and pharmacists need to acquire the latest knowledge. As the number of medical institutions using genetic tests increases, there is a demand for more comprehensive educational programs.
3. Patient understanding and consent
Patients undergoing genetic testing must be fully informed of the significance of the test and how to interpret the results. In particular, because genetic information may be related to the risk of future illnesses, it is important to have a support system in place to reduce the psychological burden on patients.
The future of genetic testing and aspirin therapy
1. Utilizing big data and genetic information
In recent years, advances in big data analysis technology have enabled the analysis of vast amounts of genetic information and research into optimal treatment for individual patients. In particular, large-scale genome-wide association studies (GWAS) are being used to discover new gene polymorphisms that may affect aspirin responsiveness.
This method makes it possible to compare the genetic information of tens to hundreds of thousands of patients and identify gene mutations related to the prevention of cardiovascular disease. For example, recent studies have suggested that in addition to PTGS1, ITGB3, and PEAR1 , genes such as GUCY1A3 and ALOX5AP may also be related to the effects of aspirin.
2. Gene editing technology and cardiovascular disease prevention
With the development of gene editing technologies such as CRISPR-Cas9, it may be possible in the future to reduce the risk of cardiovascular disease at the genetic level. For example, gene editing may be used to improve the efficacy of aspirin in patients with genetic polymorphisms that reduce the effectiveness of aspirin.
Currently, this technology is primarily applied to the treatment of genetic diseases, but research is underway to examine whether it can also be applied to prevent cardiovascular disease.
3. Personalized medicine through the integration of AI and genetic information
By utilizing artificial intelligence (AI) to comprehensively analyze genetic information, lifestyle data, and medical records, more precise personalized medicine will become possible.
For example, a system is being developed in which AI combines and analyzes the following data to propose individual treatment plans:
Genetic polymorphism information (genes that affect the effectiveness of aspirin)
Blood test data (platelet count, clotting factor levels, etc.)
Lifestyle information (diet, exercise, smoking, drinking, etc.)
Existing disease data (diabetes, hypertension, dyslipidemia, etc.)
If such a system were implemented in clinical practice, it would enable doctors to select the most appropriate antiplatelet therapy for each patient, enabling them to better manage the risk of cardiovascular events.
Case study of aspirin therapy using genetic testing
1. Efforts in the United States
A large-scale genetic research project called The Million Veteran Program (MVP) is currently underway in the United States. This project is analyzing the genome data of approximately one million American veterans to assess their risk of various diseases, including cardiovascular disease.
As part of this research, efforts are underway to identify genetic polymorphisms involved in aspirin responsiveness, and it is hoped that these will be utilized in the formulation of future treatment guidelines.
2. Trends in Japan
In Japan, the National Cerebral and Cardiovascular Center and the Tohoku Medical Megabank Organization are working to develop medical treatments that utilize genetic information. In particular, research is being conducted to investigate differences in the effectiveness of aspirin due to genetic polymorphisms, and treatments that take into account the genetic background unique to Asians are being developed.
In addition, an increasing number of companies are introducing genetic testing as part of health checkups, and in the future, personalized medicine using genetic testing may become more widespread even in general medical institutions.
Advantages and disadvantages of genetic testing from the patient’s perspective
Merit
Enabling selection of optimal treatment plan
Patients who do not respond well to aspirin can be identified and alternative therapies considered.
This helps avoid unnecessary medications and reduces the risk of side effects.
Realizing personalized medicine
This will enable treatment based on each patient’s genetic characteristics.
The accuracy of preventive medicine will improve, minimizing the risk of cardiovascular events.
Reducing future medical costs
Preventing inappropriate use of medications can reduce wasteful medical costs.
This enables early detection and prevention, reducing the burden of long-term medical expenses.
Disadvantages
Cost of testing
At present, genetic testing is expensive and only a limited number of cases are covered by insurance.
Psychological burden
Being informed of the risk of future disease based on the results of genetic testing can be psychologically stressful for patients.
Privacy issues
Appropriate management is required for the handling of genetic information.
There is a risk that genetic information will be provided to third parties without the patient’s consent, so legislation needs to be put in place.
Future challenges and prospects
In order for genetic testing to be widely used in the medical field in the future, the following points need to be improved:
Reducing testing costs and expanding insurance coverage
Advances in testing technology are expected to make it possible to provide low-cost, highly accurate genetic tests.
Education of healthcare professionals
It is important to train doctors and pharmacists who can properly interpret the results of genetic tests and explain them to patients in an easy-to-understand manner.
Accumulation of evidence
More clinical trials are needed to verify the effectiveness of genetic testing and aspirin treatment.
Legal and ethical development
The legal framework regarding the management of genetic information will be strengthened and mechanisms to protect patient privacy will be established.
The potential of preventive medicine using genetic testing
The use of genetic testing will not only help evaluate the effectiveness of aspirin, but will also have a significant impact on the prevention of cardiovascular disease in general. In particular, identifying gene polymorphisms related to arteriosclerosis and thrombosis will enable the risk assessment of each patient and the implementation of appropriate preventive measures.
1. Construction of a cardiovascular risk score
Currently, indices for assessing risk of cardiovascular disease, such as the Framingham Risk Score and ASCVD Risk Score, are used, but these are mainly based on clinical data such as age, sex, smoking history, blood pressure, and cholesterol levels.
However, by adding genetic information, it is possible to create a more accurate risk score. For example, it is known that people with a mutation in the LPA gene have higher blood levels of lipoprotein(a) and a higher risk of arteriosclerosis. Taking this into account, more accurate risk prediction is possible.
2. Personalized lifestyle guidance
Based on the results of genetic testing, we can provide optimal lifestyle advice for each patient. For example, the following approaches may be considered according to genetic risk:
If aspirin resistance is high, switch to another antiplatelet drug or adjust the dose.
If you are at high risk of developing blood clots, strengthen your exercise habits and give dietary advice (intake of omega-3 fatty acids is recommended)
If you are at high risk of hypertension → If you have high genetic sensitivity to sodium, we recommend that you give more advice on reducing salt intake.
In this way, if it becomes possible to provide individualized guidance based on genetic information, more effective preventive medical care will be realized.
Genetic testing and public health
It is important to utilize genetic testing not only in medical practice but also from a public health perspective, as incorporating genetic information into screening and prevention programs for high-risk populations could improve the health management of society as a whole.
1. Introduction to workplace health checks
An increasing number of companies are introducing genetic testing as part of their employee health management. For example, by providing appropriate health guidance to employees who have genetic characteristics that make aspirin less effective, future medical expenses can be reduced.
2. Cooperation with the health insurance system
Including genetic testing within the scope of health insurance coverage will make it easier for more people to undergo testing. For example, in Japan, specific health checkups (metabolic syndrome checkups) are conducted, and incorporating genetic testing into these would enable more detailed risk assessments.
The importance of communication with patients
When conducting genetic testing, it is essential to communicate appropriately with patients. In particular, the following points should be noted:
Helping people understand the significance of genetic testing
Explain that “genes do not determine everything” and also emphasize the importance of environmental factors.
Help them understand that genetic test results are not a definitive diagnosis but are part of a risk assessment.
Psychological care
Some patients become anxious when they are told that they have a genetic high risk of cardiovascular disease, so they need psychological support.
Provide appropriate follow-up to prevent patients from worrying more than necessary.
Privacy Protection
Since genetic information is extremely sensitive for individuals, appropriate data management is required.
It is important to obtain the patient’s explicit consent when sharing genetic information with third parties.
Evolution of genetic testing technology and future prospects
1. The rise of next-generation sequencing (NGS)
Conventional genetic testing generally detects mutations in specific genes, but advances in next-generation sequencing (NGS) technology have made it possible to analyze a wider range of genetic information, which has led to progress in research into identifying previously unknown genes involved in aspirin responsiveness.
2. Application to precision medicine
The Precision Medicine Initiative, promoted by the National Institutes of Health (NIH), is working to integrate genetic information, environmental factors, and lifestyle data to realize personalized medicine. In the future, similar projects will likely expand to Japan, and the use of genetic testing to select treatment methods may become commonplace.
3. Potential for CRISPR-based gene therapy
In the future, gene editing technology may be used to develop treatments that fundamentally reduce the risk of cardiovascular disease. For example, research is being conducted on a method to reduce the risk of blood clots without relying on aspirin by activating a gene that suppresses vascular inflammation.
The future of genetic testing and personalized medicine
Advances in genetic testing technology are making individualized aspirin therapy a reality. In the future, we will likely see an era in which medical institutions and pharmaceutical companies will develop new treatment strategies using genetic information to provide optimal treatment for each patient.
Furthermore, the spread of precision medicine using AI and machine learning is expected to improve the accuracy of treatment plans tailored to individual patients. By working together with medical professionals and patients to implement treatments that utilize the latest scientific knowledge, the effectiveness of cardiovascular disease prevention and treatment can be maximized.
Summary
By utilizing genetic testing, it is possible to clarify the reasons why the effect of aspirin differs from person to person and to develop more appropriate treatment strategies. It is known that certain gene polymorphisms are involved in aspirin resistance, and personalized medicine based on this is progressing.
In addition, as precision medicine using AI and big data analysis becomes more widespread, it will become possible to develop treatment plans that take into account genetic information and environmental factors in an integrated manner. As the cost of genetic testing decreases and guidelines are established in the future, more patients should be able to benefit.
Personalized medicine using genetic information will be an important step in opening up new avenues for the prevention and treatment of cardiovascular diseases.
