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Circulating lipoprotein(a) levels and health outcomes: Phenome-wide Mendelian randomization and disease-trajectory
Susanna C Larsson1, Lijuan Wang2, Xue Li2
1Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Insights
High Lipoprotein(a) [Lp(a)] levels are linked to increased risks of circulatory diseases and anemia. This study also identified three main patterns of multiple health conditions associated with elevated Lp(a).
Area of Science:
- Genetics and Cardiovascular Epidemiology
- Metabolomics and Disease Risk
- Biomarkers and Atherosclerosis
Background:
- Lipoprotein(a) [Lp(a)] is a known risk factor for atherosclerotic and valvular diseases.
- The association of Lp(a) with a wider spectrum of diseases remains to be fully established.
- This research investigates the broader phenomic impact of circulating Lp(a) levels.
Purpose of the Study:
- To assess the association of circulating Lp(a) levels with a broad range of diseases using phenome-wide Mendelian randomization.
- To explore disease trajectories and comorbidity patterns linked to high Lp(a) levels.
- To investigate novel associations beyond established cardiovascular risks.
Main Methods:
- Constructed a weighted polygenic risk score using LPA gene variants affecting Lp(a) levels.
- Conducted Phenome-Wide Association Studies (PheWAS) in 385,917 White UK Biobank participants across 1081 phenotypes.
- Performed two-sample Mendelian randomization (MR) using FinnGen consortium data and disease-trajectory analyses.
Main Results:
- PheWAS revealed associations of higher Lp(a) with circulatory diseases (cardiac, peripheral, hypertension, valvular, cerebrovascular), endocrine/metabolic diseases (hyperlipidemia, type 2 diabetes), genitourinary diseases (renal failure), and hematologic diseases (anemia).
- MR analysis supported Lp(a) association with anemia risk and suggested a link with type 2 diabetes, but not renal failure.
- Disease-trajectory analyses identified three major morbidity patterns (cardiovascular, metabolic, mental disorders) related to high Lp(a).
Conclusions:
- Genetically predicted higher Lp(a) levels are associated with increased risk for numerous circulatory diseases and anemia.
- The study identified significant sequential patterns of multiple morbidities linked to elevated Lp(a) levels.
- These findings expand the known disease associations of Lp(a) and highlight its systemic impact.
Background:
Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerotic and valvular diseases, but its possible role in other diseases has not yet been established. We conducted phenome-wide Mendelian randomization and disease-trajectory analyses to assess any associations of circulating Lp(a) levels with a broad range of diseases.
Methods:
A weighted polygenic risk score was constructed using independent genetic variants in the LPA gene and with an established effect on Lp(a) levels. The PheWAS analysis included 1081 phenotype outcomes ascertained among 385,917 White participants of the UK Biobank. Novel findings were investigated in MR analysis using data from the FinnGen consortium. Disease-trajectory and comorbidity analyses were further conducted to explore the sequential patterns of multiple morbidities related to high circulating Lp(a) levels.
Results:
PheWAS revealed statistically significant associations of higher circulating Lp(a) levels with increased risk of a large number of circulatory system diseases (including various cardiac diseases, peripheral vascular disease, hypertension, and valvular and cerebrovascular diseases) as well as some endocrine/metabolic diseases (including hyperlipidemia, hypercholesterolemia, disorders of lipoid metabolism, and type 2 diabetes), genitourinary system diseases (renal failure), and hematologic diseases (including different types of anemia). Two-sample MR analysis supported the association between Lp(a) and risk of anemia, showed a suggestive association with type 2 diabetes, but found no association with renal failure. Disease-trajectory and comorbidity analyses identified 3 major sequential patterns of multiple morbidities, mainly in the cardiovascular, metabolic, and mental disorders, related to high circulating Lp(a) levels.
Conclusions:
Genetically predicted higher circulating Lp(a) levels were associated with increased risk of many circulatory system diseases and anemia. Additionally, this study identified three major sequential patterns of multiple morbidities related to high Lp(a).
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