Genetically predicted high-density lipoprotein traits and pan-disease risk: a systematic review

High-density lipoprotein (HDL) is a highly heterogeneous lipoprotein with multiple physiological functions. However, observational studies present conflicting evidence regarding its association with various diseases. This review systematically summarizes evidence from Mendelian randomization (MR) studies to investigate the causal relationships between HDL-related biomarkers and a wide spectrum of disease outcomes. We systematically searched multiple databases up to November 2024. The causal relationship between HDL and 158 diseases was studied. Findings reveal that the role of HDL is highly disease-specific. Genetically predicted higher HDL levels are protective against most circulatory and digestive system diseases. Conversely, however, they are associated with an increased risk of certain conditions, including breast cancer, intracerebral hemorrhage, and age-related macular degeneration. The MR analyses revealed inconsistent and sometimes conflicting findings for several disease outcomes, notably Alzheimer's disease. This review underscores the context-dependent nature of HDL's effects, which may be driven by factors like HDL particle heterogeneity and functional transformation into a pro-inflammatory state. Future research should move beyond concentration-based metrics to focus on HDL functionality and precise subtyping to fully understand its role in disease etiology.