Risk of Coronary Artery Disease Conferred by Low-Density Lipoprotein Cholesterol Depends on Polygenic Background

Bolli, Alessandro; Domenico, Paolo Di; Pastorino, Roberta; Busby, George B.J.; Bottà, Giordano

doi:10.1161/circulationaha.120.051843

Cited by 28 publications

(21 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…130–160 mg/dL) actually have the same risk as those with hypercholesterolaemia (LDL > 190 mg/dL), a condition that we could call ‘invisible hypercholesterolaemia’. 10 This phenomenon is worrisome because millions of people have LDL cholesterol levels between 130 and 160 mg/dL. In the presence of a high polygenic score, these subjects develop atherosclerotic plaques with the same intensity and risk as those with hypercholesterolaemia, but in a more subtle way, because it is invisible to traditional risk models.…”

Section: The Genetic Component Of Myocardial Infarctionmentioning

confidence: 99%

New prevention scenarios: polygenic risk

Boccanelli

Bottà²

2021

European Heart Journal Supplements

Self Cite

View full text Add to dashboard Cite

Although coronary heart disease is a highly preventable disease, it is still the leading cause of morbidity and mortality in developed countries. This is also due to the fact that the risk models used in clinical practice have proved ineffective in identifying people at risk: up to 30% of cases of myocardial infarction do not have traditional risk factors used in risk estimation models. Although the genetic component of myocardial infarction has been known for many years, with an inheritance rate of between 40% and 60%, it is not yet used as a risk factor in primary prevention models such as the Heart Card or the European SCORE. Recent advances in genomics and the use of clinical big data have allowed the development of genetic risk scores called Polygenic Risk Score (PRS), capable of identifying populations with average LDL-C levels, but with the same risk of heart attack of carriers of hypercholesterolaemia. The clinical usefulness of the PRS lies precisely in identifying high-risk individuals who are invisible to traditional models. The clinical applications of PRS for coronary artery disease are discussed in this report.

show abstract

Section: The Genetic Component Of Myocardial Infarctionmentioning

confidence: 99%

New prevention scenarios: polygenic risk

Boccanelli

Bottà²

2021

European Heart Journal Supplements

Self Cite

View full text Add to dashboard Cite

show abstract

“…In fact there appears to be a U-shaped relationship for the association of HDL-C with atherosclerotic disease, as those with the very highest HDL-C levels may have dysfunctional HDL, for example if the scavenger receptor B1 is defective, such that reverse cholesterol transport is impaired [2][3][4]. Thus, there is growing interest in HDL function, rather than its levels, as directly causal for protection from atherosclerosis [5,6]. One well-studied mechanism for HDL's loss of function is through its oxidation by myeloperoxidase (MPO) [7], with about 1 in 5 HDL molecules recovered from human atheroma bearing the signature of this modification [8].…”

Section: Introductionmentioning

confidence: 99%

Oxidant resistant human apolipoprotein A-I functions similarly to the unmodified human isoform in delaying atherosclerosis progression and promoting atherosclerosis regression in hyperlipidemic mice

et al. 2022

View full text Add to dashboard Cite

Background Transgenic overexpression of apolipoprotein A-I (apoA1) has been shown to delay atherosclerosis lesion progression and promote lesion regression in mouse models; however, apoA1 is subject to oxidation by myeloperoxidase (MPO) and loss of function. The activity of oxidant resistant human apoA1 was compared to unmodified human apoA1 in mouse models of atherosclerosis progression and regression. Methods and results Human apoA1 and the MPO oxidant resistant 4WF isoform transgenic mice were bred to LDL receptor deficient (LDLr KO) mice and fed a western-type diet. High level expression of these human apoA1 isoforms did not lead to increased HDL-cholesterol levels on the LDLr KO background. In males and females, lesion progression was studied over time, and both apoA1 and 4WF transgenic mice vs. LDLr KO mice had significant and similar delayed lesion progression and reduced non-HDL cholesterol. Using time points with equivalent lesion areas, lesion regression was initiated by feeding the mice a low-fat control diet containing a microsomal triglyceride transfer protein inhibitor for 7 weeks. Lesions regressed more in the male apoA1 and 4WF transgenics vs. the LDLr KO, but the 4WF isoform was not superior to the unmodified isoform in promoting lesion regression. Conclusions Both human apoA1 and the 4WF MPO oxidant resistant apoA1 isoform delayed lesion progression and promoted lesion regression in LDLr KO mice, with more pronounced effects in males than females; moreover, the 4WF isoform functioned similarly to the unmodified human apoA1 isoform.

show abstract

“…PRSs for coronary artery disease (CAD) are of special interest given that CAD is a highly heritable condition and the leading cause of preventable death in the developed world (11)(12)(13)(14). While there remains some debate regarding the precise utility of CAD PRSs in risk stratification (15)(16)(17)(18), high polygenic risk has been independently and repeatedly associated with enhanced benefit from lipid lowering therapy (19)(20)(21)(22)(23)(24). This allows a CAD PRS to act as a "risk-enhancer" in any CAD preventive health-decision making scenario, beyond its contribution to risk stratification (14,25,26).…”

Section: Introductionmentioning

confidence: 99%

Response to Polygenic Risk: Results of the MyGeneRank Mobile Application-Based Coronary Artery Disease Study

Chen

et al. 2021

Preprint

View full text Add to dashboard Cite

The degree to which polygenic risk scores (PRS) influence preventive health is the subject of debate, with few prospective studies completed to date. We developed a smartphone application for the prospective and automated generation, communication, and electronic capture of response to a PRS for coronary artery disease (CAD). We evaluated self-reported actions taken in response to personal CAD PRS information, with special interest in the initiation of lipid lowering therapy (NCT03277365). 20% of high genetic risk (n=95) vs 7.9% of low genetic risk individuals (n=101) initiated lipid lowering therapy at follow-up (p-value = 0.002). The initiation of both statin and non-statin lipid lowering therapy was associated with degree of genetic risk: 15.2% (n=92) vs 6.0% (n=100) for statins (p-value = 0.018) and 6.8% (n=118) vs 1.6% (n=123) for non-statins (p-value = 0.022) in high vs low genetic risk, respectively. Overall, degree of genetic risk was associated with use of any lipid lowering therapy at follow-up: 42.4% (n=132) vs 28.5% (n=130) (p-value = 0.009). We also find that CAD PRS information is perceived to be understandable, actionable, and does not induce health anxiety.

show abstract

Risk of Coronary Artery Disease Conferred by Low-Density Lipoprotein Cholesterol Depends on Polygenic Background

Cited by 28 publications

References 5 publications

New prevention scenarios: polygenic risk

New prevention scenarios: polygenic risk

Oxidant resistant human apolipoprotein A-I functions similarly to the unmodified human isoform in delaying atherosclerosis progression and promoting atherosclerosis regression in hyperlipidemic mice

Response to Polygenic Risk: Results of the MyGeneRank Mobile Application-Based Coronary Artery Disease Study

Contact Info

Product

Resources

About