Is ‘good’ cholesterol bad for Age-related Macular Degeneration? Evidence from the EYE-RISK and E3 Consortia

Abstract

Purpose : Lipids including cholesterol are highly concentrated in drusen. Genetic epidemiologic studies have shown that typical lipid genes are implicated in AMD, and have provided evidence that blood levels of High Density Lipoproteins (HDL), the lipoprotein which is protective for cardiovascular disease, is elevated in patients with AMD. We studied circulating lipids and cholesterol levels in relation to AMD in a very large European dataset, and investigated whether this relationship may be driven by certain sub fractions.

Methods : The EYE-RISK/E3 database included data from 14 European studies on AMD phenotype (Early and Late AMD), genetic risk variants, medication history, and systemic lipid and cholesterol levels (N= 41764). The Rotterdam Study had data available (N=1500) on lipid sub fractions which had been identified in plasma by the Nightingale biomarker platform. Lipid sub fractions were +1log transformed and standardized. Generalized linear mixed-effects model incorporating confounders and study site as a random effect was used to estimate the associations between systemic lipids and AMD.

Results : HDL and triglycerides were associated in opposite directions with Early or Late AMD, corrected for age, sex, body mass index, smoking, and study site (HDL Odds Ratio (OR) 1.19 per 1 mmol/L increase (95% confidence interval [CI] 1.13-1.26,); triglycerides OR 0.94 per 1 mmol/L increase [95% CI 0.91-0.96]. Total cholesterol and LDL were not significantly associated to AMD. With respect to 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 gene risk variant (rs17231506) was positively associated (beta=0.16 (p=1.1x10^-7), while LIPC risk variants (rs2043085, rs2070895) were negatively associated with the proportion of extra-large HDL particles (beta’s=-0.14 and -0.13 p=9.7x10^-7 and 1.5x10^-4 respectively). Lipid lowering drugs was not associated with AMD (p=0.17).

Conclusions : Our data suggest that high systemic HDL was associated with an increased risk of AMD, and triglycerides decreased this risk. The largest HDL particles appeared to be drivers of this association, and may be controlled by the lipid and AMD genes CETP and LIPC. Whether systemic cholesterol and lipids are a direct cause of AMD, or are biomarkers for a local disease process in the retina is an intriguing next question.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.