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The effects of eight serum lipid biomarkers on age-related macular degeneration risk: a Mendelian randomization study
Xikun Han1,2, Jue-Sheng Ong1, Alex W Hewitt3,4
1Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Background:
Age-related macular degeneration (AMD) is a leading cause of vision loss. Whereas lipids have been studied extensively to understand their effects on cardiovascular diseases, their relationship with AMD remains unclear.
Methods:
Two-sample Mendelian randomization (MR) analyses were performed to systematically evaluate the causal relationships between eight serum lipid biomarkers, consisting of apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], triglycerides (TG) and non-HDL cholesterol (non-HDL-C), and the risk of different AMD stages and subtypes. We derived 64-407 genetic instruments for eight serum lipid biomarkers in 419 649 participants of European descent from the UK Biobank cohort. We conducted genome-wide association studies (GWAS) for 12 711 advanced AMD cases [8544 choroidal neovascularization (CNV) and 2656 geographic atrophy (GA) specific AMD subtypes] and 5336 intermediate AMD cases with 14 590 controls of European descent from the International AMD Genomics Consortium.
Results:
Higher genetically predicted HDL-C and ApoA1 levels increased the risk of all AMD subtypes. LDL-C, ApoB, CHOL and non-HDL-C levels were associated with decreased risk of intermediate and GA AMD but not with CNV. Genetically predicted TG levels were associated with decreased risk of different AMD subtypes. Sensitivity analyses revealed no evidence for directional pleiotropy effects. In our multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results.
Conclusion:
These results suggest the role of lipid metabolism in drusen formation and particularly in AMD development at the early and intermediate stages. Mechanistic studies are warranted to investigate the utility of lipid pathways for therapeutic treatment in preventing AMD.
Insights
Lipid metabolism influences age-related macular degeneration (AMD) risk. Higher high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) increase AMD risk, while other lipids like LDL-C may decrease it.
Area of Science:
- Ophthalmology
- Genetics
- Metabolic Research
Background:
- Age-related macular degeneration (AMD) is a primary cause of vision loss.
- The role of lipids in AMD pathogenesis is not well understood, unlike their established role in cardiovascular diseases.
Purpose of the Study:
- To investigate the causal relationships between eight key serum lipid biomarkers and the risk of developing different stages and subtypes of AMD.
- To systematically evaluate genetic associations using Mendelian randomization.
Main Methods:
- Two-sample Mendelian randomization (MR) analyses were conducted.
- Genetic instruments for eight serum lipid biomarkers (ApoA1, ApoB, CHOL, HDL-C, LDL-C, Lp(a), TG, non-HDL-C) were derived from the UK Biobank (419,649 participants).
- Genome-wide association studies (GWAS) were performed on 12,711 advanced AMD cases (including CNV and GA subtypes) and 5,336 intermediate AMD cases against 14,590 controls from the International AMD Genomics Consortium.
Main Results:
- Elevated genetically predicted levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) were associated with an increased risk of all AMD subtypes.
- Lower levels of low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), total cholesterol (CHOL), and non-HDL cholesterol were linked to a reduced risk of intermediate and geographic atrophy (GA) AMD, but not choroidal neovascularization (CNV).
- Genetically predicted triglycerides (TG) showed a decreased risk association with AMD subtypes. Sensitivity analyses confirmed no significant directional pleiotropy.
Conclusions:
- Lipid metabolism plays a significant role in the development of AMD, particularly in the early and intermediate stages, potentially through drusen formation.
- Further mechanistic studies are needed to explore the therapeutic potential of targeting lipid pathways for AMD prevention.
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