Dataset Information

Clinical Implications of Monogenic Versus Polygenic Hypercholesterolemia: Long-Term Response to Treatment, Coronary Atherosclerosis Burden, and Cardiovascular Events.

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; P_adj=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.

SUBMITTER: D'Erasmo L

PROVIDER: S-EPMC8200757 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Clinical Implications of Monogenic Versus Polygenic Hypercholesterolemia: Long-Term Response to Treatment, Coronary Atherosclerosis Burden, and Cardiovascular Events.

D'Erasmo Laura L Minicocci Ilenia I Di Costanzo Alessia A Pigna Giovanni G Commodari Daniela D Ceci Fabrizio F Montali Anna A Brancato Francesca F Stanca Ilaria I Nicolucci Antonio A Ascione Andrea A Galea Nicola N Carbone Iacopo I Francone Marco M Maranghi Marianna M Arca Marcello M

Journal of the American Heart Association 20210423 9

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 identif ...[more]

PMID: 33890476

Similar Datasets

Project description:ImportanceMonogenic familial hypercholesterolemia (FH) is associated with lifelong elevations in low-density lipoprotein cholesterol (LDL-C) levels and increased risk of atherosclerotic cardiovascular disease (CVD). However, many individuals with hypercholesterolemia have a polygenic rather than a monogenic cause for their condition. It is unclear if a genetic variant for hypercholesterolemia alters the risk of CVD.ObjectivesTo assess whether a genetic variant for hypercholesterolemia alters the risk of atherosclerotic CVD and to evaluate how this risk compares with that of nongenetic hypercholesterolemia.Design, setting, and participantsIn this genetic-association, case-control, cohort study, individuals aged 40 to 69 years were recruited by the UK Biobank from across the United Kingdom between March 13, 2006, and October 1, 2010, and followed up until March 31, 2017. Genotyping array and exome sequencing data from the UK Biobank cohort were used to identify individuals with monogenic (LDLR, APOB, and PCSK9) or polygenic hypercholesterolemia (LDL-C polygenic score >95th percentile based on 223 single-nucleotide variants in the entire cohort). The data were analyzed from July 1, 2019, to December 30, 2019.Main outcomes and measuresThe study investigated the association of genotype with the risk of coronary and carotid revascularization, myocardial infarction, ischemic stroke, and all-cause mortality among the overall study population and among participants with monogenic FH (n = 277), polygenic hypercholesterolemia (n = 2379), or hypercholesterolemia with undetermined cause (n = 2232) at comparable levels of LDL-C measured at study enrollment.ResultsFor the 48 741 individuals with genotyping array and exome sequencing data, the mean (SD) age was 56.6 (8.0) years, and 54.5% were female (n = 26 541 of 48 741). A monogenic FH variant for hypercholesterolemia was found in 277 individuals (0.57%, 1 in 176 individuals). Participants with monogenic FH were significantly more likely than those without monogenic FH to experience an atherosclerotic CVD event at 55 years or younger (17 of 277 [6.1%] vs 988 of 48 464 [2.0%]; P < .001). Compared with the general population, both monogenic and polygenic hypercholesterolemia were associated with an increased risk of CVD events. Moreover, among individuals with comparable levels of LDL-C, both monogenic (hazard ratio, 1.93; 95% CI, 1.34-2.77; P < .001) and polygenic hypercholesterolemia (hazard ratio, 1.26; 95% CI, 1.03-1.55; P = .03) were significantly associated with an increased risk of CVD events compared with the risk of such events in individuals with hypercholesterolemia without an identified genetic cause.Conclusions and relevanceThe findings of this study suggest that among individuals with hypercholesterolemia, genetic determinants of LDL-C levels may impose additional risk of CVD. Thus, understanding the possible genetic cause of hypercholesterolemia may provide important prognostic information to treat patients.

Project description:BackgroundPolygenic risk scores (PRS) are associated with atherosclerotic cardiovascular disease (ASCVD) events. We studied incident ASCVD among individuals with absent coronary artery calcium (CAC = 0), to investigate the association of PRS with incident ASCVD among such individuals.MethodsData was used from Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study of participants free of clinical CVD at baseline. PRS were developed based on a literature-derived list of single-nucleotide polymorphisms (SNPs) weighted by effect size. The coronary heart disease (CHD) PRS contained 180 SNPs, and the stroke PRS had 32 SNPs. These SNPs were combined to compute an ASCVD PRS. The PRS were calculated among 3132 participants with CAC = 0. Multivariable-adjusted Cox proportional hazards models evaluated the association between each PRS (top 20% vs bottom 50%) and ASCVD.ResultsThe study population included 3132 individuals with CAC = 0 [mean (SD) age 58 (9) years; 63% female, 33% White, 31% Black, 12% Chinese-American, 24% Hispanic]. Over a median follow-up of 16 years, there were 108 incident CHD events and 93 stroke events. ASCVD event rates were generally <7.5 per 1000-person years for all ASCVD events regardless of PRS risk stratum. The ASCVD PRS was significantly associated with incident ASCVD: (HR; 95% CI) (1.63; 1.11, 2.39). The CHD PRS was not associated with any ASCVD outcome, whereas the stroke PRS was significantly associated with ASCVD (1.84; 1.27, 2.68), CHD (1.79; 1.05, 3.06), and stroke (1.96; 1.19, 3.23). The stroke PRS results were significant among women and non-Whites.ConclusionsAmong individuals with CAC = 0, the ASCVD PRS was associated with incident ASCVD events. This appears to be driven by genetic variants related to stroke but not CHD, and particularly among women and non-Whites. ASCVD event rates remained below the threshold recommended for consideration for initiation of statin therapy even in the high PRS groups.

Dataset Information

Clinical Implications of Monogenic Versus Polygenic Hypercholesterolemia: Long-Term Response to Treatment, Coronary Atherosclerosis Burden, and Cardiovascular Events.

Publications

Clinical Implications of Monogenic Versus Polygenic Hypercholesterolemia: Long-Term Response to Treatment, Coronary Atherosclerosis Burden, and Cardiovascular Events.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets