Polygenic Hypercholesterolemia

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Hypercholesterolemia causes atherosclerotic vascular disease leading to the development of coronary artery disease, transient ischemic attack, stroke, and peripheral artery disease. Polygenic hypercholesterolemia is a familial condition where there is an elevation in serum cholesterol levels due to mutation in several small LDL raising alleles. The mutation is detected using 12 single nucleotide polymorphisms (SNP) score. Polygenic hypercholesterolemia is asymptomatic and is detected during routine screening. Primary care physicians and cardiologists play an important role in evaluating and treating patients to reduce complications of the disease. The activity describes the evaluation and treatment of polygenic hypercholesterolemia by primary care physicians (PCPs) and cardiologists.


  • Describe the causes of polygenic hypercholesterolemia.
  • Review the signs and symptoms of polygenic hypercholesterolemia.
  • Summarize the treatment for polygenic hypercholesterolemia.
  • Outline the importance of consulting with an inter-professional team of specialists in the care of patients with polygenic hypercholesterolemia.


Coronary heart disease and stroke are the two leading causes of death worldwide and by the year 2030, they are projected to account for nearly 25% of deaths. Association of hypercholesterolemia with these two conditions makes it a major contributor to the global disease burden and cardiovascular disease associated with mortality and morbidity.

Hypercholesterolemia is a condition wherein the combination of genetic mutations and environmental factors like an excessive amount of fat in diet, obesity and physical inactivity lead to elevated serum cholesterol levels. Familial hypercholesterolemia is a condition where a mutation in genes LDLR, APOB, PCSK genes cause an elevation in levels of total cholesterol and LDL-C. Diagnosis of FH needs the following criteria - increased cholesterol levels, physical stigmata e.g tendon xanthomas or evidence of these signs in first or second-degree relatives and a family history of premature coronary artery disease. In approximately 60% the mutation is negative in the above-mentioned genes, leading to a polygenic cause of hypercholesterolemia. Hypercholesterolemia of genetic origin negative for mutations in LDLR, APOB, PCSK9 genes is Polygenic hypercholesterolemia. The mutation in several small LDL raising alleles ( single nucleotide polymorphism genes) leads to polygenic hypercholesterolemia which can be determined by genetic score.

Familial hypercholesterolemia leads to early development of atherosclerotic cardiovascular disease which include coronary artery disease, transient ischemic attack, stroke, peripheral artery disease. The risk is lower in polygenic variety than monogenic type.[1][2][3][4]


Mutations in several small LDL raising alleles cause polygenic hypercholesterolemia. Polygenic hypercholesterolemia is asymptomatic. It neither causes severe atherosclerosis nor presents with cardiovascular disease at an early age. Polygenic hypercholesterolemia is asymptomatic and is usually diagnosed during a routine screening and after further evaluation of abnormal lab values. Since it is genetically inherited, it runs in families. But lifestyle factors also play a major role such as a diet rich in saturated fat, lack of exercise, etc.[5]


In United States, 53% have elevated LDL-C levels which is more than 100 million of the US population. Only 50% of them receive treatment and less than 35% achieve adequate control of the blood cholesterol levels. This places them at increased risk for atherosclerotic cardiovascular disease. 

Further LDL-C is more commonly elevated in females(32%) than males (31%). Ethnic differences include - Hispanic males (38.8%), non-Hispanic black males(30.7%), non-hIspanic white males (29.4%). Prevalence is more among Asian Indians, Filipinos, Japanese, and Vietnamese than among whites.[5][6]


Mutations in LDL-C affecting genes (SNPs) cause polygenic hypercholesterolemia. Global Lipid Genetic Consortium has identified about 95 loci which affect LDL-C levels. These loci contribute not only to variation in lipid traits but also to extreme lipid phenotypes. Accumulation of several small LDL-C raising alleles leads to polygenic hypercholesterolemia. The 12 SNPs used in the score is shown below.

Global Lipid Genetic Consortium 12 SNP LDL-C Gene Score, showing the LDL-C-raising allele and the published raising effect (in mmol/l). 

Once these SNPs have been genotyped, they are entered into a scoring scheme to quantify their cumulative effect on the lipid trait. These scores sum the expected effect of each individual SNP in a given patient, yielding a polygenic SNP score (also called a ‘polygenic risk score’ or ‘polygenic trait score’) that can be compared to a normolipidaemic population. An individual with a high polygenic score, e.g., >90th percentile for the population, would be predisposed to develop clinically apparent dyslipidaemia.

After VLDL is synthesized from free fatty acids and triglycerides in the liver, it is cleaved into IDL(intermediate density lipid) and LDL. LDL is a major cholesterol-containing lipoprotein which causes atherosclerosis. LDL receptor in the liver regulates the serum cholesterol levels.

A decrease in serum cholesterol levels causes increased expression of hepatic LDL which causes greater clearance of dietary cholesterol. Increased dietary fatty acids lead to decreased expression of hepatic LDL receptors and increase serum cholesterol levels. High dietary cholesterol suppresses endogenous cholesterol production. High dietary fat will result in high serum cholesterol levels.[7][8][9][10][11][12] 

History and Physical

Polygenic hypercholesterolemia is asymptomatic and is usually detected during routine screening. It is more common in individuals with a family history, but also lifestyle factors also play a major role. History should include cigarette smoking, diabetes mellitus, and sedentary lifestyle assessment since they also contribute to the clinical manifestation of the disease.


The current recommendation for screening for hypercholesterolemia is starting from age 21 if they have risk factors (level B). Risk factors include smoking, high blood pressure, diabetes mellitus, BMI>30, family history of premature cardiovascular disease or previous personal history of atherosclerotic cardiovascular disease). It is repeated every 5 yrs, if normal. HDL and total cholesterol levels are measured if non-fasting which can be used to estimate atherosclerotic cardiovascular disease risk score. If the cholesterol levels are moderately elevated, dietary changes are recommended for 4-6months. If high the patient is started on lipid-lowering therapy.

Strong recommendation(Level A) is from age 35 for males and age 45 for females.

Determination of LDL-C mutation causing alleles and determination of genetic score is recommended to detect polygenic hypercholesterolemia. 

 The degree of thickening in the carotid artery as measured by ultrasound, as well as coronary calcium score is less in polygenic hypercholesterolemia when compared to monogenic hypercholesterlemia. [6][3][6]

Treatment / Management

Statins have significantly reduced coronary artery disease rates, TIA rates and strokes. 

Statins inhibit the enzyme HMG-CoA reductase. They decrease LDL, thereby reducing mortality. 

Examples include - Atorvastatin, rosuvastatin, pitavastatin decrease LDL by >50% (high intensity statins)

Lovastatin, simvastain, decrease LDL moderately (moderate intensity statins, decrease LDL between by 30%-50%)

Fluvavastatin, pravastatin decrease LDL mildly (decrease LDL-C by <30%)

Bile acid sequestrants

Cholestyramine, cholesterol, cloesevelam.

They bind to bile acids and decrease absorption of cholesterol and increase LDL receptors. 

 PCSK9 inhibitors - Alirocumab and Evolocumab cause a decrease in LDL cholesterol levels through decreased degradation of LDL receptors. 

Ezetimibe - It selectively inhibits cholesterol absorption in the intestine by binding to the Niemann-Pick C1-Like 1 (NPC1L1) protein.

Exercise along with decreased intake of dietary saturated fat aid in decreasing the prevalence of high serum cholesterol and atherosclerotic cardiovascular disease.  [13][14][15][16][15][6][15][17][15]

Differential Diagnosis

Familial Hypercholesterolemia (tendon xanthomas)

Hypertryglyceridemia ( eruptive xanthomas)

Secondary hypercholesterolemia in the following conditions

- Liver disease

- Hypothyroidism

- Nephrotic syndrome

- Chronic renal disease

- Hypopituitarism

- Systemic lupus erythematosus

- Alcoholism

- Cigarette smoking

- Storage diseases like Gaucher disease, Von Gierke disease[5]

Toxicity and Side Effect Management


Side effects of statins include - 

statin associated myalgia

statin induced myopathy ( management includes decreasing the dose, weekly long acting statin, start a different statin, or switch to other class of hypolipidemic agent)

rhabdomyolysis (needs immediate treatment to decrease renal injury, evaluate for other co-morbidities, triggering factor, assess for medications which interfere with metabolism of statins)

statin associated autoimmune myopathy ( discontinue statin)

new onset diabetes mellitus(risk is more in patients with metabolic syndrome- it is discussed with the patient before stating the drug)

hepatic failure(discontinue)

memory and cognition changes

gastrointestinal side effects

respiratory infections. 

PCSK9 inhibitors - side effects include nasopharyngitis, injection site reactions.

NPC1L1 blocker - ezetimibe 

Side effects - headache, URIs, myalgia, fatigue, weakness, increase in liver enzymes, diarrhea. 

myopathy (when used with statin in patients >65yrs, renal impairment, hypothyroidism)

Bile acid sequestrants 

side effects - They decrease absorption of fat soluble vitamins, constipation, bloating, indigestion, vomiting. 

When taking other medications they should be spaced 4-6hrs apart to decrease the chance of impaired absorption. [14][16][17][16][18][16]


Transient ischemic attack (TIA)


Coronary artery disease (CAD)

Peripheral artery disease (PAD)



Genetic consult 


Deterrence and Patient Education

Medication adherence

Dietary recommendations on low fat and low cholesterol diet is recommended[5]

Enhancing Healthcare Team Outcomes

Polygenic hypercholesterolemia is an autosomal dominant familial condition wherein mutation in several small LDL raising alleles leads to an elevation in serum cholesterol levels. The condition is asymptomatic and is usually detected on routine screening. Other causes for increased serum cholesterol include familial hypercholesterolemia, hypercholesterolemia secondary to liver disease, hypothyroidism, nephrotic syndrome, chronic renal disease, hypopituitarism.

While PCP plays an important role in evaluation and treatment, it is important to consult with an inter-professional team of specialists which include cardiologists and geneticists. The pharmacist will ensure whether the patient is on a hypolipidemic agent.

Proper evaluation and treatment will lead to a reduction in TIA, strokes, CAD, and PVD.[14] 

Article Details

Article Author

Meenakshi Narayanaswamy

Article Editor:

Saurabh Sharma


6/27/2022 11:47:10 PM



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