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 hun-dred 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 hyper-cholesterolemia is helpful in providing important prognostic information.
Clinical implications of monogenic versus polygenic hypercholesterolemia: Long-term response to treatment, coronary atherosclerosis burden, and cardiovascular events / D'Erasmo, L.; Minicocci, I.; Di Costanzo, A.; Pigna, G.; Commodari, D.; Ceci, F.; Montali, A.; Brancato, F.; Stanca, I.; Nicolucci, A.; Ascione, A.; Galea, N.; Carbone, I.; Francone, M.; Maranghi, M.; Arca, M.. - In: JOURNAL OF THE AMERICAN HEART ASSOCIATION. CARDIOVASCULAR AND CEREBROVASCULAR DISEASE. - ISSN 2047-9980. - 10:9(2021). [10.1161/JAHA.120.018932]
Clinical implications of monogenic versus polygenic hypercholesterolemia: Long-term response to treatment, coronary atherosclerosis burden, and cardiovascular events
D'erasmo L.Primo
;Minicocci I.;Di Costanzo A.;Pigna G.;Commodari D.;Ceci F.;Montali A.;Brancato F.;Nicolucci A.;Ascione A.;Galea N.;Carbone I.;Francone M.;Maranghi M.;Arca M.
2021
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 hun-dred 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 hyper-cholesterolemia is helpful in providing important prognostic information.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
