A recent research has highlighted how having elevated LDL cholesterol levels does not represent the same risk of developing coronary heart disease for all individuals, but it is variable from person to person, based on the genetic profile. In other words, if a person’s genes are not prone to developing coronary atherosclerotic disease, the damage caused by high LDL cholesterol levels is limited. The study was published in recent days, with free access, in the journal Circulation.
Studies of the human genome
There are different approaches to the study of the human genome. One of these is what is commonly called a genome-wide association study, an investigation of the genes presents in the cells of an individual, to determine any peculiar differences, compared to a series of other individuals. Differences that can then be associated with the development of specific diseases.
These genome-wide studies are generally performed by evaluating 100,000 variants of a single nucleotide, the constituent element of DNA, through the hybridization of samples obtained from subjects with the disease and from healthy subjects.
However, this method has some limitations, because the detection of particular variants can have a modest predictive value towards the disease, and because the frequency with which a particular variant is found is not able to distinguish between patients and controls. In other words, for example, even if a particular variant is more frequent in subjects with coronary heart disease, this same variant can also be present in subjects will not develop it.
The polygenic risk score
The Polygenic Risk Score (PRS) was developed to improve the predictive value of genome-wide studies. In this test, combinations of variants are used in order to multiply their predictive value for a disease. It is based on the principle that if the predictive value of each of these genetic variants is small, adding them together will make the disease risk prediction more reliable.
The number of variants of a single nucleotide included in the test can vary from small sets, which contain less than 10 variants, but the more significant analyze sets with over 100,000 variants. It should also be considered that, based on the formula used to calculate the PRS, if the number of variants increases, the predictive power of the test correspondingly decreases.
In this new study, the researchers developed a new method of calculating the PRS for coronary heart disease, capable of evaluating the importance of single nucleotide polymorphism, thanks to calculations based on a test conducted on the whole genome and then compared with a set of reference data. The result was a PRS algorithm that included 300,238 single nucleotide polymorphisms.
Genetic risk and LDL cholesterol
The researchers then divided the subjects included in the trial in three groups based on their PRS: high, intermediate, and low. Subsequently, the subjects were classified on the basis of LDL cholesterol values.
The results obtained clearly highlight how the risk of developing coronary heart disease due to high LDL cholesterol levels is not the same in all the people evaluated but differs, according to the risk emerged in the calculation of the PRS.
It was clearly evidenced that subjects with a low genetic risk do not present a significant predisposition to the development of coronary heart disease, not even for LDL cholesterol values higher than 190 mg/dL.
Conversely, individuals with a high genetic risk, i.e., with a high PRS, show a greater risk of developing the disease, even if LDL cholesterol levels are between 100 and 129 mg/dL.
For subjects included in the intermediate genetic risk group, the increased risk of coronary heart disease is observed for LDL cholesterol values between 130 and 159 mg/dL.
The comparison between individuals with intermediate and high PRS, showed that the increase in the risk of disease, for any LDL cholesterol value, is almost double in the second group.
The importance of genes
This new study clearly evidenced what is the real burden of the risk conferred by genes for the development of coronary heart disease, compared to that conferred by “external” factors. The burden of genes in determining the development of this pathological condition is predominant, even when compared with that of LDL cholesterol, normally considered one of the main risk factors for the disease.
The research scientifically expresses what can be commonly observed in clinical practice. On the one hand there are subjects with particularly high cholesterol who do not develop an atherosclerotic disease, on the other hand, subjects with substantially normal cholesterol values but who have a widespread disease. Certainly these are two extreme situations, not representative of the majority of the population, but they provide an idea of how complex the interaction between genetic and non-genetic factors is in the development of a disease.
The authors conclude by suggesting that the greatest benefits from lipid-lowering treatments can be obtained in patients with high PRS and that the evaluation of this score can be done from a young age, thus selecting people who need early preventive interventions.
If we were able to identify a PRS with a strong predictive power for the most important diseases, not just cardiovascular ones, we would probably be able to implement a targeted and effective disease prevention.
The complete knowledge of the human genome, and the ability to analyze it with simple and reliable methods, probably represents the future of medicine. A future that appears ever closer.
This post is also available in: Chinese (Simplified)