With each new publication, our understanding of the genetic predisposition to diseases is becoming more sophisticated. At the start of the 20th century, the most advanced scientific evidence suggested that consuming large amounts of meat, eggs, and milk caused atherosclerosis in experimental animals, which is characterized by the accumulation of fats and other substances in the blood, and was soon associated with high cholesterol levels. Since then, science has made significant strides, leading to the development of numerous medical action guides, new ways of detecting hypercholesterolemia, and new treatments. In Brazil, the Longitudinal Study of Adult Health (ELSA), a long-term research project that began in 2008, is contributing to this new paradigm, particularly with regards to genetic predisposition to some diseases. The project is a collaborative effort among six Brazilian universities, including the University of São Paulo, Federal University of Rio Grande do Sul, Oswaldo Cruz Foundation (Fiocruz) in Rio de Janeiro, Federal University of Espírito Santo, Federal University of Minas Gerais, and Federal University of Bahia. As part of this partnership, the Laboratory of Genetics and Molecular Cardiology recognized the need to better understand how genetic predisposition is linked to the risk of developing certain cardiovascular diseases, with a focus on the PCSK9 enzyme. This research was conducted in 2021.
PCSK9, what is it?
PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) is a protein that plays an important role in cholesterol metabolism. It is primarily produced in the liver and acts to regulate the degradation of LDL (Low-Density Lipoprotein) receptors, also known as “bad” cholesterol. These receptors are responsible for capturing circulating LDL cholesterol in the blood, reducing its quantity and thus preventing the accumulation of fat in the arteries. Under normal conditions, PCSK9 facilitates the internalization of LDL receptors into cells, where cholesterol is destroyed. However, when there is an excessive production of PCSK9, normal recycling of receptors is impeded, and more receptors are destroyed, thus increasing the amount of LDL cholesterol in the blood.
Cardiovascular risk factors and PCSK9
As we have seen so far, PCSK9 has a close relationship with cholesterol, which we are fully familiar with as it relates to our lifestyle. However, even when we follow a healthy lifestyle and adopt measures to maintain adequate cholesterol levels, we may still have a high risk of developing cardiovascular diseases. This is where inhibiting the action of the PCSK9 gene can play an important role in preventing these diseases. Through specific medications that block the abnormal function of PCSK9, it is possible to significantly reduce LDL cholesterol levels in the blood and decrease the risk of serious cardiovascular events such as heart attack, stroke, and other problems related to the heart and blood vessels.The task of finding PCSK9 in our vast genome
In 2021, the Laboratory of Genetics and Molecular Cardiology conducted research that assessed factors already known to be associated with cardiovascular diseases. As in other studies, researchers found a relationship between LDL cholesterol and total cholesterol. Other factors, such as sex, age, race, and smoking – a significant lifestyle-related risk factor – were also evaluated, but showed no relationship with abnormal PCSK9 levels in the blood. The most significant discovery of this study was found in the genome. Researchers focused on evaluating the genome locations where PCSK9 abnormalities occur, and for that, they used a technique called co-localization. This technique is commonly used in genetic studies to determine if different genetic variants are associated with the same genome region. Co-localization analysis can lead to the identification of genes or variants that cause a particular condition or characteristic. Scientists observed that if something was affecting changes in patients’ cholesterol levels, the answer could be found in chromosomes 1, 7, 12, and 14 – which are complex structures made of a single molecule of highly coiled DNA. They also identified four potentially related genes. These findings bring us closer to the possibility of more precise treatments and the identification of genetic factors has become pivotal in establishing new disease predictors and identifying new targets for drugs.Other sources
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