Polygenic Risk Score - High LDL Cholesterol

Cholesterol is important in human health, serving as both a vital component of cellular membranes and a precursor to essential molecules like hormones.  However, excessive cholesterol, particularly LDL cholesterol, isa risk factor for cardiovascular disease.  

Low-density lipoprotein (LDL) cholesterol, often referred to as "bad" cholesterol, is a type of lipoprotein responsible for transporting cholesterol particles throughout the bloodstream. It consists of a lipid core containing cholesterol esters and triglycerides, encased within a phospholipid and protein shell.

LDL cholesterol delivers cholesterol to various cells and tissues in the body, where it contributes to membrane structure and serves as a precursor for the synthesis of steroid hormones, bile acids, and vitamin D.  However, elevated LDL cholesterol levels pose a significant risk factor for atherosclerosis and coronary artery disease.

Elevated LDL cholesterol levels signal a condition known as hypercholesterolemia which can result from various factors including genetic predisposition, dietary choices rich in saturated and trans fats, sedentary lifestyle, obesity, and certain medical conditions like diabetes, hypothyroidism, and kidney disease.

This informational article aims to delve into the intricacies of LDL cholesterol, exploring its definition, functions, clinical significance, and methods for managing its levels.

Definition and Function of LDL Cholesterol

What is LDL Cholesterol? 

LDL, or “low-density lipoprotein” cholesterol, is a type of cholesterol particle known as a non-HDL cholesterol particle.

In the water-soluble bloodstream, lipids must travel inside lipophilic compartments.  A lipid particle, or lipoprotein, refers to a microscopic structure composed of lipids, which are fats or fat-like substances, and proteins. These particles serve as carriers for lipids throughout the body, transporting them through the bloodstream and facilitating their utilization or storage in various tissues.

These lipoprotein particles are characterized by the lipoproteins attached to them, as well as their direction (efflux, meaning out to peripheral tissues, or influx, meaning towards the liver).  

HDL or “healthy cholesterol” particles are characterized by the presence of ApoA lipoproteins, as well as their direction: HDL particles are influx particles, meaning they transport peripheral cholesterol back to the liver for processing.  

LDL particles are a type of non-HDL particle.  Non-HDL particles include very low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], low-density lipoprotein [LDL], and lipoprotein(a), or Lp(a).  

These particles all contain Apo-B lipoproteins and are efflux particles, meaning they travel from the liver to peripheral tissues.  They are also small enough to cause atherosclerosis; for all of these reasons, they are considered to increase cardiovascular risk.  [2.]

Function of LDL Cholesterol: What Does LDL Cholesterol Do in the Body?

LDL cholesterol particles travel in the bloodstream, transporting cholesterol to cells for repair.  Unfortunately, LDL cholesterol is also a primary cause of cholesterol deposition within artery walls. 

Extensive research supports the pivotal role of low-density lipoprotein (LDL) in ASCVD pathogenesis, as highlighted by consensus statements.  [3.] 

LDL's atherogenicity involves modulating factors influencing its interaction with the arterial wall and downstream effects within arterial tissue. While LDL's primary role is acknowledged, emerging evidence suggests the involvement of other apolipoprotein B-containing lipoproteins in ASCVD pathophysiology.

LDL’s Entry into the Arterial Intima  [3.]

LDL's journey into the arterial intima involves transcytosis across the endothelium, a process influenced by various factors including sex hormones, inflammatory pathways, and metabolic conditions. Once in the intima, LDL retention occurs primarily through interactions with arterial wall proteoglycans, initiating the formation of atherosclerotic lesions, particularly in regions exposed to disturbed blood flow.

Furthermore, LDL particles exhibit considerable heterogeneity in their physicochemical and functional properties, contributing to their atherogenicity. 

Small dense LDL particles, in particular, display prolonged residence time in circulation and heightened affinity for arterial wall components, enhancing their atherogenic potential. The interplay between LDL subfractions, metabolic conditions, and genetic factors further complicates the understanding of ASCVD risk.

The progression of atherosclerosis is intricately linked to the retention and modification of low-density lipoprotein (LDL) in the arterial wall. LDL retention initiates a cascade of events leading to lesion development. 

LDL Cholesterol Retention and Lesion Development  [3.]

LDL particles, particularly susceptible to oxidation in the subendothelial matrix, generate oxidized LDL (oxLDL), which triggers a sterile inflammatory response. This response activates endothelial cells, inducing the recruitment of monocytes that differentiate into macrophages. 

These macrophages further promote LDL oxidation and internalization, forming cholesterol-laden foam cells. Additionally, the presence of other LDL modifications and other mechanisms contribute to macrophage foam cell formation.

The immune response to retained and modified LDL involves T cells and B cells infiltrating the arterial wall. CD4+ Th1 cells promote atherogenesis, countered by T regulatory cells expressing anti-inflammatory cytokines. 

B cells produce antibodies, some of which target oxLDL, modulating inflammation. Targeting these immune responses presents a potential therapeutic approach to halt atherogenesis.

Efficient efferocytosis, the clearance of dying cells by phagocytes, plays a crucial role in resolving inflammation. However, in atherosclerosis, defective efferocytosis leads to the accumulation of apoptotic cells, promoting necrosis and sustaining inflammation. 

LDL Cholesterol and Thrombosis  [3.]

Plaque stability is influenced by the composition and architecture of the plaque tissue. Lesions with substantial lipid cores are prone to rupture, while erosion of plaques lacking lipid cores can also lead to thrombosis. Lowering LDL levels mitigates key mechanisms of plaque instability, emphasizing the importance of LDL-lowering therapies in atherosclerosis management.

The balance of plaque formation vs. resolution is delicate and nuanced.  Because of this, multiple therapeutic targets are available, although preventing the initial entry of non-HDL particles including LDL particles into arterial intima should be a major consideration for clinicians.  

What Causes High LDL Cholesterol?

Lifestyle

An unhealthy lifestyle is the most common cause of high LDL cholesterol.  This includes a diet high in saturated fats, a sedentary lifestyle, and smoking, which all raise LDL cholesterol levels.  Additionally, excessive stress and/or alcohol may raise LDL cholesterol.  

Genetic Causes

Familial hypercholesterolemia (FH): FH is a genetic disorder characterized by high levels of LDL cholesterol from birth, leading to premature atherosclerosis and increased risk of cardiovascular disease. It is typically caused by mutations in genes encoding the LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9).  [6.]

Familial defective apoB-100 (FDB): FDB is a rare genetic disorder caused by mutations in the APOB gene, resulting in impaired binding of LDL particles to LDL receptors. This leads to elevated levels of LDL cholesterol in the blood and an increased risk of cardiovascular disease.  [37.]

Autosomal recessive hypercholesterolemia (ARH): ARH is a rare genetic disorder characterized by mutations in the LDLRAP1 gene, which impairs the internalization of LDL particles by cells. Individuals with ARH have high LDL cholesterol levels and are at increased risk of premature heart disease.  [1.]

Sitosterolemia (phytosterolemia): Sitosterolemia is a rare genetic disorder caused by mutations in either the ABCG5 or ABCG8 genes, leading to impaired excretion of plant sterols and cholesterol. This results in elevated levels of both LDL cholesterol and plant sterols in the blood, which can cause premature atherosclerosis and cardiovascular disease.  [41.]

Autosomal dominant hypercholesterolemia (ADH): ADH is a genetic disorder characterized by high levels of LDL cholesterol due to mutations in the LDLR gene. It is inherited in an autosomal dominant pattern, meaning that a person only needs to inherit one copy of the mutated gene to develop the condition.  [42.]

Polygenic hypercholesterolemia: Polygenic hypercholesterolemia refers to high LDL cholesterol levels caused by the combined effect of multiple genetic variants across different genes involved in lipid metabolism. It is more common than monogenic forms of hypercholesterolemia and often presents later in life.  [20.]

Familial combined hyperlipidemia (FCHL): FCHL is a genetic disorder characterized by elevated levels of LDL cholesterol, triglycerides, and total cholesterol, along with low levels of HDL cholesterol. It is inherited in an autosomal dominant pattern and is associated with mutations in genes involved in lipid metabolism, although the exact genetic basis is not fully understood.  [26.]

Familial dysbetalipoproteinemia (type III hyperlipoproteinemia): Familial dysbetalipoproteinemia is a genetic disorder characterized by elevated levels of cholesterol and triglycerides due to impaired clearance of remnant lipoproteins. It is caused by mutations in the APOE gene and is associated with an increased risk of premature atherosclerosis and cardiovascular disease.  [14.]

Other Medical Conditions

Hypothyroidism: Hypothyroidism, or underactive thyroid, can lead to elevated LDL cholesterol levels as thyroid hormones play a crucial role in lipid metabolism. Reduced thyroid hormone levels can slow down the clearance of LDL cholesterol from the bloodstream.  [35.]

Nephrotic Syndrome: Nephrotic syndrome, a kidney disorder characterized by proteinuria, can cause high LDL cholesterol levels due to increased hepatic production of lipoproteins and decreased clearance of LDL from the circulation.  [39.]

Obesity: Obesity is often associated with high LDL cholesterol levels. Excess adipose tissue leads to dysregulation of lipid metabolism, resulting in increased LDL cholesterol production and decreased clearance.  [6.]

Polycystic Ovary Syndrome (PCOS): PCOS, a hormonal disorder common in women of reproductive age, can be associated with high LDL cholesterol levels.  It’s thought to be due to insulin resistance and hormonal imbalances, although the etiology is not confirmed.  [17.]

Cholestasis: liver disorders, especially cholestasis, disrupt cholesterol metabolism and can lead to various forms of hypercholesterolemia, including the appearance of Lp-X. Mistaking Lp-X for LDL cholesterol can disrupt accurate cardiovascular risk assessment and result in unnecessary lipid-lowering therapy. 

Lp-X, also known as lipoprotein-X, is an abnormal lipoprotein particle found in the bloodstream. It is typically composed of phospholipids, free cholesterol, and apolipoprotein B, but lacks normal lipid constituents like triglycerides and cholesterol esters. Lp-X is often seen in conditions of liver dysfunction, particularly cholestasis, and its presence can interfere with accurate measurement of LDL cholesterol levels, potentially leading to misinterpretation of cardiovascular risk.

Regular lipid panel assessments, including apo B-100 measurement, are essential for liver transplant (LT) recipients, both during evaluation and post-transplantation. Apo B-100 measurement aids in distinguishing between atherogenic and non-atherogenic hypercholesterolemia, providing valuable insights into cardiovascular risk and the effectiveness of therapy, particularly in the context of coexisting cholestasis and Lp-X with true atherogenic hypercholesterolemia after lipid therapy.  [23.]

Anorexia Nervosa: Individuals with anorexia nervosa may develop high LDL cholesterol levels due to malnutrition and starvation. Decreased caloric intake can lead to increased hepatic production of cholesterol and altered lipid metabolism.  [43.]

Medications

Protease inhibitors: Certain antiretroviral medications used to treat HIV/AIDS, such as lopinavir and ritonavir, can lead to elevated cholesterol levels.  [32.]

Thiazide diuretics: While effective for managing high blood pressure and fluid retention, thiazide diuretics can sometimes raise cholesterol levels, especially LDL cholesterol.  [36.]

Atypical antipsychotics: atypical antipsychotics, used to treat psychiatric disorders like schizophrenia and bipolar disorder, can sometimes lead to elevated cholesterol levels.  However, different medications may have different metabolic effects.  [28.]

Isotretinoin: This medication, commonly prescribed for severe acne, has been associated with elevated cholesterol and triglyceride levels in some individuals.  [7.]

‍Immunosuppressants: Drugs used to suppress the immune system following organ transplantation, such as cyclosporine and tacrolimus, may contribute to elevated cholesterol levels.  [18.]

Oral contraceptives: certain birth control pills can increase cholesterol levels, especially LDL cholesterol.  [22.] 

‍Antidepressants: Some antidepressant medications, such as tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), might contribute to alterations in cholesterol metabolism, though the effects can vary among individuals.  [34.]

Lab Testing for LDL Cholesterol Levels

General Testing Information and Sample Type

Typically, cholesterol assessment starts with a lipid panel, which includes the following biomarkers: total cholesterol, LDL and HDL cholesterols, and triglycerides.

People are increasingly aware of the benefits of advanced testing for cholesterol levels in order to support wellness, reduce their risk of cardiovascular disease, and inform personalized medical decisions.  To address the desire for more information about cholesterol health, lab companies are increasingly offering more comprehensive assessments.  

A few examples include:

The Cardiometabolic Profile by Doctor’s Data

The CadioPro Advanced Profile by Access Medical Labs

The Cardiometabolic Comprehensive Profile by BostonHeart Diagnostics

The LPP Plus by Spectracell Laboratories

These tests, including the standard lipid profile, are all blood tests that require a venipuncture.  Fasting is typically recommended for these tests.  In some cases, a mobile phlebotomist can come to you to have the blood draw performed from the home or office, and the sample can then be taken to the lab by the phlebotomist. 

Interpreting Test Results

Reference Range for LDL Cholesterol

The reference range for LDL-C levels for adults are set at the following:  [16.]

Optimal: less than 100 mg/ dL

Near optimal/above optimal: 100 to 129 mg/dL

Borderline high: 130 to 159 mg/dL

High: 160 to 189 mg/dL

Very high: greater than 190 mg/dL 

Clinical Significance of High Levels of LDL Cholesterol

Cholesterol goals may be lower in patients at high risk for coronary heart disease.  [21.]

High cholesterol is also called hypercholesterolemia, and should be addressed appropriately.  

Research indicates a direct relationship between serum total cholesterol and LDL cholesterol levels and the incidence of coronary heart disease (CHD), with higher cholesterol levels correlating with increased atherosclerosis and CHD risk across populations.  [10.]

Therapies may include diet and lifestyle adjustments, supplementation, and/or medication may be considered to reduce cholesterol levels, and consequently the individual’s risk of heart disease.

Clinical Significance of Low Levels of LDL Cholesterol 

There is no agreed-upon consensus regarding what level is considered too low when it comes to cholesterol.  

Low cholesterol levels have been associated with an increased risk of certain health complications, including hemorrhagic stroke, and may be associated with some cancers. [12., 27., 40.] 

Therefore, monitoring and addressing low cholesterol levels are crucial to prevent potential adverse health outcomes and ensure overall well-being.

Related Biomarkers: What Should Be Tested Besides Total Cholesterol?

The standard lipid panel is a good place to begin to evaluate an individual’s risk of developing heart disease.  There are a variety of other biomarkers available that can provide increased information above and beyond a standard lipid panel.  Some of these include: 

VLDL Particles: very-low-density lipoprotein (VLDL) particles are a precursor to LDL particles and play a crucial role in lipid metabolism. Elevated VLDL levels are associated with increased risk of atherosclerosis and cardiovascular disease.  [9.]

Total LDL Particles (LDL-P): measuring the number of LDL particles gives different information than LDL-C, which is the amount of cholesterol that’s carried by LDL particles.  

Knowing the number of LDL particles present in the bloodstream provides a more comprehensive assessment of cardiovascular risk than LDL-C alone because the size of LDL particles also confers cardiovascular risk, with smaller LDL particles being more atherogenic.  

Therefore, in two people with the same LDL-C number, the person with a higher LDL-P (and therefore more small LDL particles present in his or her bloodstream) has a higher risk for a cardiovascular event than the person with the lower LDL-P.  [24.]

Remnant Lipoprotein: remnant lipoproteins, remnants of VLDL and chylomicrons after triglyceride hydrolysis, are atherogenic particles associated with increased risk of cardiovascular events, even in individuals with normal LDL cholesterol levels.  [25.]

Dense LDL III and Dense LDL IV: small dense LDL (sdLDL) subfractions, particularly LDL III and LDL IV, are more atherogenic than larger, buoyant LDL particles. Measuring these subfractions provides additional information for assessing cardiovascular risk beyond traditional lipid panels.  [30.]

Buoyant HDL 2b: buoyant HDL 2b particles are considered particularly cardioprotective due to their role in reverse cholesterol transport. Higher levels of buoyant HDL 2b are associated with reduced risk of cardiovascular events.  [13.]

Lipoprotein(a): Elevated lipoprotein(a) levels are an independent risk factor for cardiovascular disease, particularly in individuals with a family history of premature heart disease.  It is important to note that Lp(a) levels are genetically determined and change little, if at all, in response to diet and lifestyle.  [33.]

Apolipoprotein B (ApoB): Apolipoprotein B is a structural component of atherogenic cholesterol particles including VLDL, IDL, LDL and Lp(a)  particles and is considered a more accurate predictor of cardiovascular risk compared to LDL cholesterol levels alone, particularly in the setting of insulin resistance and diabetes.  [2.]

Apolipoprotein A1 (apoA1): apoA1 is attached to the surface of HDL particles, and is associated with a cardioprotective effect.  Elevated apoA1 levels are associated with improved HDL functionality and reduced cardiovascular risk, while low levels are independently linked to increased risk of cardiovascular events. 

Monitoring apoA1 levels allows for better risk prediction and assessment of therapeutic efficacy in managing cardiovascular disease risk.

hs-CRP (High-Sensitivity C-Reactive Protein): elevated hs-CRP levels are indicative of systemic inflammation and are associated with increased risk of cardiovascular events, including myocardial infarction and stroke.  [11.]

Homocysteine: elevated homocysteine levels are associated with increased risk of cardiovascular disease, including atherosclerosis, stroke, and venous thromboembolism.  [31.]

How to Support Healthy Cholesterol Levels

Lifestyle Modifications

• Maintain a healthy weight through regular physical activity and a balanced diet.  [45.]
• Reduce sedentary behavior and incorporate more movement throughout the day to support a healthy metabolism.
• Manage stress levels through relaxation techniques such as meditation or yoga. High stress has been correlated with metabolic dysfunction.  [44.]
• Ensure adequate sleep duration and quality to support metabolic health.  [38.]

Dietary Changes  [8.]

• Consume a diet rich in whole foods, including fruits, vegetables, whole grains, lean proteins, and healthy fats.  
• Limit intake of highly processed foods, sugary beverages, and foods high in saturated and trans fats.
• Increase fiber intake from sources like legumes, nuts, seeds, and whole grains to promote satiety and regulate blood sugar levels.
• Monitor portion sizes and practice mindful eating to prevent overeating and promote weight management.
• Follow a plant-based diet, and reduce intake of high-fat animal products. 

Exercise Recommendations  [19.]

• Engage in a combination of aerobic exercise, strength training, and flexibility exercises to improve metabolic function.
• Aim for regular physical activity throughout the week, incorporating both cardiovascular exercise and resistance training sessions.
• Gradually increase exercise intensity and duration over time to challenge the body and promote fitness gains.
• Incorporate activities you enjoy to increase adherence to exercise routines and maintain long-term consistency.
• Consult with a healthcare provider or fitness professional to develop a personalized exercise plan based on individual fitness levels and health goals.

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