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Qiao Fan, Gemmy Cheung, Chiea Chuen Khor, E Shyong Tai, Chi Pui Pang, Kyu Hyung Park, Nagahisa Yoshimura, Tien Yin Wong, Ching-Yu Cheng, Genetics of AMD in Asians (GAMA) Consortium; The role of lipoprotein cholesterol in age-related macular degeneration: an instrumental variable approach using multiple genetic variants. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):790.
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Lipid metabolism, particularly high-density lipoprotein cholesterol (HDL-c), has been implicated in the pathogenesis of age-related macular degeneration (AMD). We aim to determine whether plasma lipid levels are causally associated with the risk of neovascular AMD in East Asians using a two-sample multiple instrumental variables (IVs) approach in a context of Mendelian randomization analysis.
We considered common genetic variants in 42 distinct loci (IVs) for lipoprotein cholesterol recently identified from genome-wide association studies (P < 5 X 10-8) in East Asians, such as LPL, CETP, LIPC, APOE and APOB. The reported beta coefficients on each genetic variant for either HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) or triglycerides were employed as the first stage regression coefficients. The risk for AMD at each of these 42 variants was estimated in independent samples as the second stage regression coefficients, using a meta-analysis of genetic association studies on 2,242 neovascular AMD cases and 4,495 controls from the Genetics of AMD in Asians (GAMA) Consortium. The diagnosis of neovascular AMD was made based on clinical examinations using dilated fundus photography, fluorescent angiography and optical coherence tomography. IV estimation at each genetic variant used the two-stage least square estimator. The causal effect of HDL-C, LDL-C, TC and triglycerides on risk of AMD was quantified by combining the IV estimators of each variant employing inverse-variance weights.
Using multiple IVs approach, we observed a causal association between higher HDL-C and an increased risk of neovascular AMD (odds ratio [OR] = 1.63, per standard deviation increase in HDL-C; P = 9.20 x 10-3). The causal effect of HDL-C on AMD risk was greatly attenuated if CETP rs3764261 was omitted from the IVs (OR = 1.07, P = 0.701). LDL-c (P = 0.533), TC (P = 0.966) and triglycerides levels (P = 0.644) were not causal risk factors for AMD.
Our results shows that HDL-C level may influence risk of AMD and CETP could play a role in this process. Whether the observed causal association could be due to a pleiotropic effect of CETP in the various functional pathways underlying HDL-c and AMD needs further investigation.
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