| Title: | Factorial Mendelian randomization of lipoprotein (a) lowering, low-density lipoprotein cholesterol lowering, and lifestyle improvements: joint associations with cardiovascular risk |
| Journal: | International Journal of Epidemiology |
| Published: | 16 Feb 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40064167/ |
| DOI: | https://doi.org/10.1093/ije/dyaf020 |
| URL: | https://academic.oup.com/ije/article-pdf/54/2/dyaf020/62369895/dyaf020.pdf |
Publication 15257
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Abstract
BACKGROUND: High levels of lipoprotein(a) [Lp(a)] have been associated with an increased risk of cardiovascular disease (CVD); however, the effects of Lp(a)-lowering therapy in combination with low-density lipoprotein cholesterol (LDL-C)-lowering treatment or lifestyle improvements on CVD risk remain unexplored.</p>
METHODS: We conducted a factorial Mendelian randomization study among 385 917 participants in the UK Biobank. Separate genetic scores were constructed to proxy the effects of Lp(a) lowering, LDL-C lowering through different targets [HMG-CoA reductase, NPC1-like intracellular cholesterol transporter 1, proprotein convertase subtilisin/kexin Type 9, and low-density lipoprotein receptor (LDLR)], as well as improvements in body mass index (BMI), systolic blood pressure (SBP), and lifestyle factors (cigarette smoking, alcohol consumption, and physical activity).</p>
RESULTS: Genetically predicted lower Lp(a) levels were associated with a decreased risk of CVD and CVD-specific mortality. Per 50-mg/dl, the hazard ratio ranged from 0.73 [95% confidence interval (CI): 0.73, 0.73] for peripheral artery disease (PAD) to 0.95 (95% CI: 0.92, 0.99) for venous thromboembolism. In factorial analyses exploring combined exposure to low-level Lp(a) and low-level LDL-C, there was no consistent evidence for departure from an additive model for any outcome (Pinteraction > .05), with the exception of the analysis using the LDLR score and PAD (Pinteraction = .006). In factorial analyses exploring combination therapies integrating Lp(a) lowering with interventions on BMI, SBP, and lifestyle factors, there was no evidence for departure from an additive model in any analysis (Pinteraction > .05).</p>
CONCLUSIONS: Our study suggests that Lp(a) lowering will have a similar magnitude for reducing cardiovascular events whether it is considered alone, or in conjunction with LDL-C reduction or lifestyle improvements.</p>
15 Keywords
- Adult
- Aged
- Body Mass Index
- Cardiovascular Diseases
- Cholesterol, LDL
- Female
- Heart Disease Risk Factors
- Humans
- Life Style
- Lipoprotein(a)
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Polymorphism, Single Nucleotide
- United Kingdom
10 Authors
- Lijuan Wang
- Fangyuan Jiang
- Jing Sun
- Jianhui Zhao
- Yazhou He
- Dipender Gill
- Stephen Burgess
- Susanna C Larsson
- Shuai Yuan
- Xue Li
1 Application
| Application ID | Title |
|---|---|
| 10775 | Phenome-wide association study (PheWAS) for the investigation of the associations between serum vitamin D levels and multiple health outcomes |
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