Angiotensin converting enzyme (ACE) is a protein in the body that creates the molecule angiotensin II. Angiotensin II increases blood pressure by causing blood vessels to constrict and by causing the kidneys to retain water. ACE inhibitors are a type of drug commonly used to treat high blood pressure (hypertension). By decreasing the activity of ACE, the levels of angiotensin II are reduced, and blood pressure is lowered. Some patients do not respond to these drugs because of variations in the genes that code for the ACE protein.
Genes are present in all human cells. They are composed of deoxyribonucleic acid (DNA). The genes provide instructions for making proteins, which are responsible for the structure and function of cells, tissues, and organs. While any two individuals share about 99.9% of the same genes, differences do exist (except in identical twins). These differences are called gene variants, or polymorphisms, and are caused by small changes in the DNA code of the genes. The small changes may be inherited from a parent or may occur as a random mutation in the gene.
Polymorphisms in the gene that provides instructions for making the ACE protein can result in the production of more or less ACE protein. This may produce high blood pressure that does not respond well to treatment with ACE inhibitor medications. Examples of these medications include captopril, enalapril, and lisinopril. Some studies have also linked ACE polymorphisms to an increased risk of heart attack, kidney disease, and Alzheimer's disease. The mechanism underlying the effect of elevated levels of ACE protein and these disorders is poorly understood but may involve damage to blood vessels from uncontrolled high blood pressure.
Polymorphisms in the ACE gene that result in higher levels of the ACE protein in the blood appear to occur in all races. However, the effect is not the same in all races. In Caucasians and Asians, the ACE polymorphism results in higher levels of protein in the blood, meaning that if these patients require treatment for high blood pressure, they will not respond to ACE inhibitors. However, African Americans may have the same gene variant, but it has no effect on blood protein levels in this population, and therefore, ACE inhibitors work in this population. The reason for this difference is unclear.
Polymerase chain reaction: Polymerase chain reaction (PCR) is a method that uses a small amount of genetic material, or DNA, and makes millions of copies of it. A small sample of cells is taken from a blood sample or from a swab of the inside of the mouth. The genetic material is copied hundreds of times to create a larger sample, which is required to examine the DNA for gene polymorphisms.
After the gene of interest, in this case the angiotensin converting enzyme (ACE) gene, is copied by PCR, a signaling molecule called a probe is added. The probe interacts with a specific polymorphism of the ACE gene. There are many different polymorphisms, and each of them requires a unique probe. The probe has a signal attached to it, which may be a radioactive molecule or fluorescent molecule that can be detected to determine whether the ACE gene variant is present and in what quantity.
Gel electrophoresis: Gel electrophoresis is another method of detecting gene polymorphisms. DNA from the patient's blood is mixed with proteins that cut the DNA molecule into multiple pieces of different sizes. Some of the ACE gene polymorphisms will be cut into larger pieces, while different polymorphisms will be smaller. The DNA is then inserted into a gel with an electrical charge in it. The electrical charge causes the DNA particles to travel through the gel. The particles travel at different speeds because of differences in their size and charge. Each polymorphism can be identified based on how it moves within the gel. After gel electrophoresis has been performed, a fluorescent marker is added that highlights the location of the DNA within the gel. Based on the location of a segment of DNA, scientists can determine whether a gene polymorphism is present.
Testing for ACE gene polymorphisms is not used in general medical practice. Currently, both of these methods are primarily used in research laboratories.
Researchers are working to determine the effect of angiotensin converting enzyme (ACE) gene polymorphisms on the risk of some types of disease. It is currently unclear whether ACE polymorphisms increase the risk of heart attack, heart failure, kidney failure, or stroke. If a link can be found, it may be beneficial to test patients for these gene variants.
Research is also being performed to determine whether testing for ACE polymorphisms is useful in patients with high blood pressure. Some patients may have high blood pressure that is caused by ACE gene variants, or they may fail to respond to a type of medication called ACE inhibitors because of variations in their ACE gene that cause them to produce more ACE protein than normal. If an individual produces more ACE protein, ACE inhibitors cannot effectively block all of the protein. Research is being performed to determine whether testing for ACE polymorphisms would be beneficial by giving doctors better information to determine which drugs to use in treating patients with these gene variants. There are other types of drugs available that may work in these patients, including beta-blockers, such as propranolol, and diuretics, such as Lasix®.
Currently, testing for angiotensin converting enzyme (ACE) gene polymorphisms is used only in research. Once these polymorphisms are better understood, however, testing for the ACE gene variants will allow doctors to identify patients who have variants that put them at a higher risk of high blood pressure. High blood pressure is dangerous if left untreated because it can cause damage to the heart, kidneys, and blood vessels. Researchers can also use this information to identify patients who are likely to be resistant to ACE inhibitor drugs, and to consider other types of medication in these patients.
Angiotensin converting enzyme (ACE) gene polymorphisms are poorly understood. There is debate among scientists about how important these polymorphisms are. Some studies have linked ACE gene variants to heart attacks, heart failure, kidney failure, and Alzheimer's disease, but other studies have reported no link between ACE polymorphisms and these diseases. The reason for these conflicting results is unclear. Scientists must gain a better understanding of ACE polymorphisms and how they affect health before testing for these gene variants can become widespread.
Research is ongoing to determine the association of angiotensin converting enzyme (ACE) gene polymorphisms with several different diseases, including high blood pressure, heart attacks, heart failure, kidney failure, and Alzheimer's disease. A clearly identified link between the genetic variants and a disease may lead to the use of genetic testing to identify patients at risk for the disease.
Only a few different types of polymorphisms that can affect the ACE gene have been identified. Researchers are working to determine whether additional polymorphisms can also occur. If other polymorphisms are identified and found to have an effect on the function of the ACE gene, then testing for these genetic variants may prove to be useful.
The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.