Familial Hypercholesterolemia (Low-Density Lipoprotein Receptor (LDLR) Variants)

what is the mode of inheritance for familial hypercholesterolemia?

autosomal semidominant disorder of lipoprotein metabolism

what is the main pathogenic variant gene that leads to familial hypercholesterolemia?

LDLR gene

what does the a mutation in the LDLR gene result in?

accumulation of high plasma levels of LDL-C

what is the prevalence of heterozygous HeFH in most populations?

1 in 250 to 300 in most populations

what are founder population in familial hypercholesterolemia?

Quebecois, Christian Lebanese, and Afrikaners

significantly higher prevalence due to limited genetic diversity

what are LDLs?

-a species of spheroidal, macromolecular lipoproteins that carry lipids within plasma

-others include high density lipoproteins (HDL), very low density lipoprotein (VLDL), and chylomicrons

what does chronically high LDL-C levels lead to?

accelerate the growth of arterial wall plaques that can rupture and cause occlusion, leading to premature atherosclerotic cardiovascular disease (ASCVD) end points

what are examples of atherosclerotic cardiovascular disease (ASCVD) end points?

-myocardial infarct

-stroke

-peripheral arterial disease

what is 75% of plasma cholesterol transported within?

transported within LDL particles, which are cleared by LDL receptors (LDLRs)

what are LDLR's?

-160 kD transmembrane glycoprotein of 839 amino acids

-expressed on all cell surfaces, but especially on hepatocytes

-binds apolipoprotein (apo_ B-100), which is the sole protein of LDL

-receptor ligand complex is internalized via receptor mediated endocytosis that also requires the LDLR adaptor protein 1 (LDLRAP1)

-cholesterol retain, but LDLR recycles to the cell surface to mediate uptake of LDL particles, a process that occurs repeatedly until the receptor is degraded by proprotein convertase subtilism kexin type 9 (PCSK9)

What do increased levels of LDL-C in FH patients result from?

-reduced LDLR activity, usually caused by different classes of pathogenic LDLR variants

-defective apo B-100 resulting from pathogenic APOB variants located within the LDLR binding domain

-gain of function PCSK9 variants, resulting in rapid degradation that hyperactivity of PCSK9 reduced LDLR numbers

what kind of inheritance do pathogenic variants in LDLR, APOB, and PCSK9 follow?

semidominant

heterozygote's phenotype is intermediate in severity between those of an individual with biallelic pathogenic variants and one with two normal alleles

where do pathogenic variants associated with FH occur?

-occur across all LDLR functional domains

-5 to 10% are copy number variants (CNVs)

-mostly large deletions

where are more than 3000 pathogenic LDLR variants archived in?

ClinVar database, accounting for 80-90% of all HeFH cases

What are the three genes that can be pathogenic variants in FH?

-LDLR

-APOB

-PCSK9

what are a majority of PCSK9 mutations in HF?

severeal missence gain-of-function variants

what is the variant in the APOB variant that accounts for FH inheritance?

p.Arg3527Cys

What other diseases/ pathogenic variants in other dyslipidemia genes can present with phenotypes that resemble HeFH?

ABCG5/8 (sitosterolemia; MIM 618666), APOE (dysbetalipoproteinemia; MIM 617347), or LIPA (lysosomal acid lipase deficiency; MIM 278000

what types of mutations/variants among LDLR variants tend to have more severe LDL-C elevation?

individuals with a CNV, splicing variant, or nonsense variant tend to have more severe LDL-C elevation compared to those with a missense variant

what are LDL-C levels strongly influenced by?

polygenic effects, meaning that common nonpathogenic single-nucleotide variant genotype with individually small effect on LDL-C act additively to raise LDL-C levels above a threshold suggestive of HeFH

what happens to LDL-C as a result of polygenic predisposition?

aggregate in families but do not follow clear inheritance patterns

background polygenic effects also exacerbate LDL-C elevation in individuals with a pathogenic HeFH variant

what does ASCVD stand for?

atherosclerotic cardiovascular disease

what can modify the effect of LDLR mutations on LDL-C levels and ASCVD risk?

environment, sex, and genetic background

how is an individual homozygous FH?

due to identical or different variants on both alleles of the same gene, or to two different variants in two different genes (digenic inheritance)

what biallelic variant can cause autosomal recessive subtype of homozygous FH?

LDLRAP1

what are symptoms/characteristics of homozygous FH?

-xanthomas expressed in the first decade

-extremely elevated LDL C

-high risk of premature ASCVD and aortic disease (can be fatal)

what is a common symptom in HeFH patients?

plasma LDL-C concentration is >95th percentile

what were symptoms in >50% of HeFH patients a generation ago?

arcus corneae, xanthelasmas, and extensor tendon xanthomas

now, it's <20%

what are the diagnostic algorithms for HeFH?

Dutch Lipid Clinic Network Criteria, the Simon Broome Register Criteria (UK), and the Canadian FH Diagnostic Criteria

Each set of criteria tallies and give weights to clinical, biochemical, and genetic features, yielding a score that translates to a "possible," "probable," or "definite" diagnosis of HeFH

what are the most consistent features of HeFH?

-elevated LDL C

-family history of dyslipidemia or early ASCVD

what percentage of those who have hypercholesterolemia have a pathogenic DNA variant?

30-60% of patients referred to a lipid clinic with suspected HeFH and LDL-C >5 mmol/L

what percentage of individuals have a pathogenic variant that have an LDL-C > 8 mmol/L?

>95%

what do treatment guidelines for HeFH focus on?

reduction of LDL-C

for primary prevention of ASCVD in HeFH patients, what do many clinical guidelines recommend?

reducing LDL-C by >50% from baseline levels

for secondary prevention of ASCVD, what are treatments?

LDL-C target levels are much stricter, usually requiring greater than or equal to 2 medications

what do all HeFH patients benefit from?

-counseling on diet

-physical activity to maintain appropriate body weight

-advice on modifications of risk factors (smoking, DM, HTN)

Why are nonpharmacologic lifestyle measures effective in managing HeFH?

reduce LDL-C by 10-20% and improve efficacy of medical therapy

what does drug treatment for HeFH center on?

oral inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase using high-intensity statin drug

what is the second agent that HeFH patients use to achieve LDL-C goals?

usually ezetimibe, an oral inhibitory of cholesterol absorption

recently approved agents that inhibit PCSK9 via either biweekly injections of monoclonal antibodies or semiannual injections of a small interfering RNA are effacious and well tolerated

why will pharmacologic therapies have limited efficacy for homozygous FH individuals?

they all require functional LDLRs, which these patients lack

what is the standard of care for patients with homozygous FH?

weekly or biweekly extracorporeal LDL removal by apheresis

orphan drug treatments include lomitapide and evinacumab (both extremely costly)

in practical terms, how does HeFH behave?

behaves as a typical fully penetrant autosomal dominant condition

what is the likelihood that each child of an affected parent will inherit the pathogenic variant?

50% chance

what are approaches to finding new HeFH cases?

population-wide screening and cascade screening

how are biochemical or DNA cascade screening of relatives of a clinically identified case important in detecting inheritance/ likelihood to pass on the variant?

-has a higher case finding rate

-50% for first degree relatives

-25% of second degree relatives

-12.5% of third degree relatives

what is the difference between cascade screening and population screening?

cascade screening focuses on families and is more targeted

populaiton screening casts a wider net but finds fewer cases