What are the causes of elevated high‑density lipoprotein (HDL) levels?

Causes of Elevated HDL Cholesterol

Elevated HDL cholesterol is primarily caused by genetic factors, regular aerobic exercise, moderate alcohol consumption, and dietary patterns emphasizing monounsaturated fats and low carbohydrates. 1

Genetic and Hereditary Factors

Genetic variation is the most significant determinant of HDL cholesterol levels, with over 25 candidate genes identified that influence HDL metabolism. 2

• Specific genetic variants in apolipoprotein A-I (the main protein component of HDL) can result in larger HDL particles and altered circulating HDL levels. 3
• Genetic variations in cholesteryl ester transfer protein (CETP) are strongly associated with elevated HDL cholesterol levels. 3
• Mutations in genes encoding lipoprotein lipases, including hepatic lipase and endothelial lipase, directly affect HDL metabolism and can lead to elevated levels. 3
• Genetic variations in paraoxonase 1 (PON1), a protein associated with HDL, influence HDL activity and levels, with effects that are genotype-dependent. 3
• Monogenic conditions causing extremely high HDL cholesterol have been identified, though most variation in the general population is oligogenic or polygenic. 2

Lifestyle and Behavioral Factors

Regular aerobic exercise significantly increases HDL cholesterol through enhanced lipoprotein metabolism and is one of the most reliable modifiable factors. 1

• Moderate alcohol consumption may raise HDL levels, though this mechanism is not recommended as a therapeutic strategy solely for HDL elevation. 1
• Low-carbohydrate diets can increase HDL levels, particularly when compared to high-carbohydrate dietary patterns. 1
• Consumption of monounsaturated fats (such as from olive oil) can increase HDL levels in some individuals, with effects that may be genotype-dependent. 3, 1

Metabolic and Physiological Considerations

The apolipoprotein A-I content largely determines plasma HDL levels, as it is the main protein component of HDL particles. 4

• HDL particle number and composition are dynamic, influenced by the complex interplay of synthesis, remodeling, and catabolism pathways. 4
• The relationship between HDL and other lipoproteins is intricate—elevated HDL often occurs in the context of low triglycerides due to inverse biological relationships. 3

Critical Clinical Caveat

Extremely high HDL cholesterol (≥116 mg/dL in men, ≥135 mg/dL in women) is paradoxically associated with increased all-cause mortality, with hazard ratios of 2.06 for men and 1.68 for women compared to optimal levels. 5

• The HDL concentration associated with lowest mortality is 73 mg/dL (1.9 mmol/L) in men and 93 mg/dL (2.4 mmol/L) in women. 5
• Extremely high HDL-C is also associated with increased risk of age-related macular degeneration and infectious diseases. 6
• No treatment is indicated to lower HDL in the absence of other lipid abnormalities, as management should focus on LDL cholesterol as the primary therapeutic target. 1

Important Distinction for Clinical Practice

Genetic studies demonstrate that HDL cholesterol levels are not causally associated with atherosclerotic cardiovascular disease, challenging the traditional "good cholesterol" paradigm. 3, 1

• While observational studies show inverse associations between HDL-C and cardiovascular risk, Mendelian randomization studies reveal this relationship is not causal when adjusted for triglycerides and LDL cholesterol. 3
• Focus clinical management on evidence-based LDL cholesterol targets rather than attempting to raise HDL levels, as randomized trials of HDL-raising therapies have failed to reduce cardiovascular events. 1