Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration

Abstract

Genetic and epidemiologic studies have shown that lipid genes and High Density Lipoproteins (HDL) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relation to AMD in a large European dataset, and investigated whether this relationship is driven by certain sub fractions. Design: (Pooled) analysis of cross-sectional data. Participants: 30,953 individuals aged 50+ participating in the E3 consortium; and 1530 individuals from the Rotterdam Study with lipid sub fraction data. Methods: In E3, AMD features were graded per eye on fundus photographs using the Rotterdam Classification. Routine blood lipid measurements were available from each participant. Data on genetics, medication and confounders such as body mass index, were obtained from a common database. In a subgroup of the Rotterdam Study, lipid sub fractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random-effect were used to estimate the associations. Main Outcome Measures: early, late or any AMD, phenotypic features of early AMD, lipid measurements. Results: HDL was associated with an increased risk of AMD, corrected for potential confounders (Odds Ratio (OR) 1.21 per 1mmol/L increase (95% confidence interval[CI] 1.14-1.29); while triglycerides were associated with a decreased risk (OR 0.94 per 1mmol/L increase [95%CI 0.91-0.97]). Both were associated with drusen size, higher HDL raises the odds of larger drusen while higher triglycerides decreases the odds. LDL-cholesterol only reached statistical significance in the association with early AMD (p=0.045). Regarding lipid sub fractions: the concentration of extra-large HDL particles showed the most prominent association with AMD (OR 1.24 [95%CI 1.10-1.40]). The CETP risk variant (rs17231506) for AMD was in line with increased-HDL levels (p=7.7x10-7); but LIPC risk variants (rs2043085, rs2070895) were associated in an opposite way (p=1.0x10-6 and 1.6x10-4). Conclusions: Our study suggests that HDL-cholesterol is associated with increased risk of AMD and triglycerides negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL sub fractions seem to be drivers in the relation with AMD, variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains a question to be answered.

Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization

“…These results confirm previous studies 23,24 that identified HDL cholesterol as a putative risk factor for AMD and draw the attention to extra-large and large HDL particles. A recent observational study 22 supports our finding that extra-large HDL particles have an important role in the pathogenesis of AMD.…”

“…Lipid particles are deposited within drusen in the different layers of Bruch's membrane in AMD patients 21 . A recent observational study has highlighted strong associations between lipid metabolites and AMD risk 22 . This evidence for lipids as potential risk factor for AMD has motivated a multivariable MR analysis which has shown that HDL cholesterol may be a putative risk factor for AMD, while there was no evidence of a causal effect for LDL cholesterol and triglycerides 23 .…”

A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration

“…Higher levels of HDL were shown in multiple studies to be associated with elevated AMD risk [29][30][31] . Our data suggest that lower predicted CETP expression is significantly associated with AMD in four tissues, but not in liver.…”

Profile-likelihood Bayesian model averaging for two-sample summary data Mendelian randomization in the presence of horizontal pleiotropy

“…Age-related macular degeneration (AMD) is a painless eye-disease that eventually leads to vision loss. Recent GWAS have identified several rare and common variants located in gene regions that are associated with lipid levels [31], fuelling speculation as to whether the relationship was causal [32,33]. To this end, a multivariable MR analysis provided evidence to support a causal relationship between AMD and HDL cholesterol but not with LDL cholesterol and triglycerides [34].…”