A polygenic risk score, developed by researchers at Italian health tech company Allelica, can identify people who may be at increased risk for heart disease despite having normal levels of LDL cholesterol.
This is important, as currently most assessments for cardiovascular disease risk primarily look at factors such as LDL cholesterol – high levels predict increased future risk for heart disease or heart attacks. These individuals may be prescribed statin drugs, which lower LDL cholesterol, to help reduce their future risk.
Doctors also look at other lifestyle factors, but genetic testing is not currently a routine inclusion in cardiovascular risk assessments unless there is a known family history of a genetic condition like familial hypercholesterolemia.
“We were interested in helping cardiologists understand why some individuals have bad arteries full of plaque while others don’t in presence of the same LDL levels and no additional risk factors,” Allelica CEO Giordano Bottà, Ph.D., told Clinical Omics.
“At present people in primary prevention with average LDL cholesterol are not considered to be at high risk and therefore they don’t start any specific prevention strategy. What we found is that more than 10% of people with average LDL have the same risk as people with hypercholesterolemia, for whom statin therapy is recommended.”
As reported in the journal Circulation, Bottà and colleagues used bioinformatics techniques combined with information collected from 408,000 individuals from the UK Biobank to build their polygenic risk score (PRS). These scores add up the risk for a specific condition associated with carriage of different genotypes for single nucleotide polymorphisms (SNPs) linked to increased risk for that disease. In this case, the PRS included a panel of 300,238 SNPs.
The researchers applied the PRS to a set of 126,499 controls and 2215 individuals who had coronary artery disease events. These individuals were split into three PRS risk groups: low (first decile; 12,872 people), intermediate (between second and ninth decile; 102,970 people) and high (top decile; 12,872 people) risk.
Taking standard risk factors like LDL cholesterol level into account, the team found that people with average LDL cholesterol levels (130-160 mg/dL) and a high PRS score had the same risk for developing coronary artery disease as those with hypercholesterolemia (LDL cholesterol above 190mg/dL) and an intermediate PRS score.
For individuals in the highest PRS risk group versus the intermediate risk group, each increase in LDL cholesterol appeared to have twice the impact, suggesting that standard recommendations for LDL cholesterol levels need to be reduced for people in this group.
“Standard risk prediction models do not consider the genetic component of cardiovascular disease. They miss a fundamental piece of information, it is like assessing risk without considering blood pressure,” says Bottà.
“For 10% of the population, just a tiny increase of LDL confers the same risk as very high levels of LDL, high enough to trigger statin intervention.”
As the UK biobank cohort is comprised mostly of individuals of European origin, the current results are mostly relevant for this group, but the research team want to test their PRS score in different groups of people in the future.
The PRS was validated in a smaller group of Africans and South and East Asians. “What we found is that in non-Europeans, the PRS is accurate but useful for a lower number of people,” says Bottà.
Allelica now wants to offer this PRS score to clinics and labs, but will aim to also do additional testing to increase the accuracy and applicability of the score. “An important next step will be understanding how these results generalize in other prospective cohorts and in populations of different ancestries,” write the article authors.