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Risk of Premature CVD in Monogenic vs. Polygenic Familial Hypercholesterolemia
Study Questions:
Is there a difference in risk of premature cardiovascular disease (CVD) in patients with heterozygous familial hypercholesterolemia (HeFH) due to a monogenic pathologic variant in low-density lipoprotein receptor (LDLR) including LDLRAP1, apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes compared to those with polygenic familial hypercholesterolemia (PFH)?
Methods:
Targeted sequencing of monogenic pathogenic variants known to cause FH as well as common LDL cholesterol (LCL-C)-raising single nucleotide genetic variants (SNVs) was performed to calculate polygenic scores in patients with “possible,” “probable,” or “definite” FH, according to Dutch Lipid Clinic Network Criteria (DLCNC) (n = 626). LDL-C weighted risk scores were calculated using the effect sizes of 28 SNVs from the genome-wide association study discovery sample. A polygenic risk score in the top 20th percentile relative to its respective 1,000 Genomes superpopulation reference was considered to have PFH. CVD variables included risk of unstable angina, myocardial infarction, coronary revascularization, or stroke occurring prior to 55 years of age.
Results:
Mean age of the overall patient cohort at enrollment was 46.2 years, 50.6% were women, and mean length of follow-up was 7.2 years. The median DLCNC score was 7 (probable FH) with a range of 5-11, and the mean baseline LDL-C was 239.0 mg/dl. Overall, a monogenic cause for FH was detected in 275 of 626 patients (43.9%) with clinically diagnosed FH, including in 11.7% of patients with “possible,” 37.4% of patients with “probable,” and 74.2% patients with “definite” FH, according to the DLCNC. A monogenic cause of FH was associated with significantly greater risk of CVD (adjusted hazard ratio, 1.96; 95% confidence interval [CI], 1.24-3.12; p = 0.004). When patients with monogenic FH-causing variants were excluded, 38.2% (n = 134 of 351) of patients had an LDL-C polygenic risk score >80th percentile of the population. The risk of CVD in patients with PFH was not significantly different compared with patients in whom no genetic cause of FH was identified. However, the presence of an elevated LDL-C polygenic risk score further increased CVD risk in patients with monogenic FH (adjusted hazard ratio, 3.06; 95% CI, 1.56-5.99; p = 0.001).
Conclusions:
Patients with monogenic FH and superimposed elevated LDL-C polygenic risk scores have the greatest risk of premature CVD. Genetic testing for FH provides important prognostic information that is independent of LDL-C levels.
Perspective:
Indeed, genetic testing has become an important clinical tool for the diagnosis of HeFH and no longer considered ‘research.’ The clinical phenotype used for the Dutch Lipid Clinic and Simon Broome estimate does not adequately separate those with HeFH from PFH. In large population cohorts, the risk of atherosclerotic CVD events is fourfold higher in those with HeFH with monogenic mutations than those who are negative even at moderately elevated levels of LDL-C (e.g., 160 mg/dl). Clinical genetic assays do not provide information regarding single nucleotide polymorphisms for the diagnosis of PFH, which becomes a diagnosis by exclusion of HeFH and other severe forms of hypercholesterolemia.
Clinical Topics: Cardiac Surgery, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Primary Hyperlipidemia
Keywords: Atherosclerosis, Angina, Unstable, Apolipoproteins B, Cholesterol, LDL, Dyslipidemias, Genetic Testing, Genome-Wide Association Study, Hypercholesterolemia, Hyperlipoproteinemia Type II, Mutation, Myocardial Infarction, Myocardial Revascularization, Nucleotides, Phenotype, Polymorphism, Single Nucleotide, Primary Prevention, Receptors, LDL, Stroke
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