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Clinical Implications of Monogenic Versus Polygenic Hypercholesterolemia: Long-Term Response to Treatment, Coronary
Laura D'Erasmo1, Ilenia Minicocci1, Alessia Di Costanzo1
1Department of Translational and Precision Medicine "Sapienza" University of Rome Rome Italy.
Insights
Monogenic familial hypercholesterolemia (FH) shows a poorer response to cholesterol-lowering therapies and increased atherosclerosis risk. Genetic testing for FH provides crucial prognostic information for patient management.
Area of Science:
- Cardiovascular Genetics
- Lipid Metabolism
- Atherosclerosis Research
Background:
- Familial hypercholesterolemia (FH) can stem from monogenic or polygenic causes.
- Understanding genetic contributions is vital for predicting therapy response and cardiovascular risk.
Purpose of the Study:
- To investigate the distinct impacts of monogenic and polygenic hypercholesterolemia on lipid-lowering therapy response.
- To assess the long-term risk of atherosclerosis and major cardiovascular events in different FH genetic subtypes.
Main Methods:
- Screening of 370 clinically diagnosed FH patients for monogenic mutations and polygenic risk scores.
- Review of medical records for therapy response and major atherosclerotic cardiovascular events.
- Coronary computed tomographic angiography in a subgroup to evaluate coronary artery calcium score and stenosis severity.
Main Results:
- Monogenic FH (FH/M+) demonstrated the poorest response to lipid-lowering therapy.
- Higher coronary artery calcium scores and prevalence were observed in FH/M+ patients compared to polygenic and control groups.
- Monogenic FH was associated with a 5-fold increased risk of major atherosclerotic cardiovascular events.
Conclusions:
- A monogenic cause of FH is linked to diminished response to conventional cholesterol-lowering treatments.
- Monogenic FH significantly increases the burden of coronary atherosclerosis and the risk of related cardiovascular events.
- Genetic testing for FH is essential for obtaining critical prognostic insights and guiding clinical decisions.
Abstract:
Background Familial hypercholesterolemia (FH) may arise from deleterious monogenic variants in FH-causing genes as well as from a polygenic cause. We evaluated the relationships between monogenic FH and polygenic hypercholesterolemia in influencing the long-term response to therapy and the risk of atherosclerosis. Methods and Results A cohort of 370 patients with clinically diagnosed FH were screened for monogenic mutations and a low-density lipoprotein-rising genetic risk score >0.69 to identify polygenic cause. Medical records were reviewed to estimate the response to lipid-lowering therapies and the occurrence of major atherosclerotic cardiovascular events during a median follow-up of 31.0 months. A subgroup of patients (n=119) also underwent coronary computed tomographic angiography for the evaluation of coronary artery calcium score and severity of coronary stenosis as compared with 135 controls. Two hundred nine (56.5%) patients with hypercholesterolemia were classified as monogenic (FH/M+), 89 (24.1%) as polygenic, and 72 (19.5%) genetically undefined (FH/M-). The response to lipid-lowering therapy was poorest in monogenic, whereas it was comparable in patients with polygenic hypercholesterolemia and genetically undetermined. Mean coronary artery calcium score and the prevalence of coronary artery calcium >100 units were significantly higher in FH/M+ as compared with both FH/M- and controls. Finally, after adjustments for confounders, we observed a 5-fold higher risk of incident major atherosclerotic cardiovascular events in FH/M+ (hazard ratio, 4.8; 95% CI, 1.06-21.36; Padj=0.041). Conclusions Monogenic cause of FH is associated with lower response to conventional cholesterol-lowering therapies as well as with increased burden of coronary atherosclerosis and risk of atherosclerotic-related events. Genetic testing for hypercholesterolemia is helpful in providing important prognostic information.
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