Plasma lipid levels and risk of retinal vascular occlusion: A genetic study using Mendelian randomization

Abstract

The causal effects of plasma lipid levels and the risk of retinal vascular occlusion (RVO) have not been clearly identified, especially for high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C). Here, we try to identify these causal risk factors using a two-sample Mendelian randomization (MR) analysis. Single nucleotide polymorphisms (SNPs) were chosen as instrumental variables (IVs). We obtained genetic variants associated with lipid exposure at the genome-wide significance (P<5×10−8) level from a meta-analysis of GWAS from the Global Lipids Genetics Consortium (GLGC) based on 188,577 individuals of mostly European ancestry for MR analyses. Meanwhile, we used lipid GWAS from UK Biobank (UKB) with a sample size of 115,078 individuals as a supplement. We obtained genetic predictors of RVO from a FinnGen biobank study. We conducted both univariable and multivariable MR (MVMR) analyses to identify the causal effects of RVO. Although inverse variance weighted (IVW) was the primary method used for MR analyses, MR–Egger and weighted-median methods were used as supplements to IVW. We determined the heterogeneity of IVs using Cochrane’s Q test and I2, and used the MR–Egger intercept and MR-PRESSO Global test to detect horizontal pleiotropy. A leave-one-out sensitivity analysis was conducted by removing a single variant from the analysis. Genetically predicted increased HDL-C level was associated with decreased risk of RVO from GLGC [OR=0.806; 95% CI=(0.659, 0.986); P=0.036], which was consistent with UKB results [OR=0.766; 95% CI=(0.635, 0.925); P=0.005]. MVMR analysis for plasma lipids [adjusted OR=0.639; 95% CI=(0.411, 0.992); P=0.046] or diabetes [adjusted OR=0.81; 95% CI=(0.67, 0.979); P=0.029] suggested that low HDL-C may be an independent risk factor for RVO. However, there was no evidence to support a causal association between LDL-C {GLGC [adjusted OR=1.015; 95% CI=(0.408, 2.523); P=0.975], UKB [OR=1.115; 95% CI=(0.884, 1.407); P=0.359]}, total cholesterol {GLGC [adjusted OR=0.904; 95% CI=(0.307, 2.659); P=0.854], UKB [OR=1.047; 95% CI=(0.816, 1.344); P=0.716]} or triglycerides {GLGC [OR=1.103; 95% CI=(0.883, 1.378); P=0.385], UKB [OR=1.003; 95% CI=(0.827, 1.217); P=0.098]} and RVO. Using two-sample MR analysis, our study suggested that dyslipidemia was a risk factor for RVO. Furthermore, our results indicated that a low HDL-C level may be an independent risk factor for RVO, suggesting that controlling HDL-C level may be effective in RVO development.

Atherogenicindex of plasma (AIP)as a Novel Biomarker to Predict Retinal Vein Occlusion

“…LDL-c leads to the initiation and progression of the atherosclerotic plaque formation in a dose-dependent manner. Therefore, LDL-c is believed to play an important role in the development of RVO [7,8]. LDL-c and total cholesterol levels were found to be elevated in the RVO group in our study; however, statistical signi cance was not reached.…”

“…In recent years, there has been a consensus that non-conventional serum lipid ratios compared to single conventional lipid parameters are better in discriminating the atherogenic events [7][8][9][10]. It has been also shown that AIP is more effective in predicting cardiovascular disorders and dyslipidemia than the single lipid parameters [11,12].…”

“…However, the precise role of dyslipidemia in the pathogenesis of RVO has not yet been fully identi ed, and only very limited data on low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and total cholesterol levels in patients with RVO is available [7][8][9]. Atherogenic index of plasma (AIP), is a novel marker of cardiovascular disease and dyslipidemia [10].…”

Causal Association between Glaucoma and Risk of Retinal Vascular Occlusion: A Mendelian Randomization Study

“…Two previous studies on risk factors in patients with RVO have used this method, making the feasibility of this study obvious. Zheng et al found a causal relationship between lipids and RVO by MR and concluded that HDL-C is a signi cant risk factor for the development of to RVO compared to other lipid types 5 . Meanwhile, using this method, Huang found that T2DM is a risk factor for RVO 24 .…”

“…The Risk factors for RVO are associated with systemic conditions such as hypertension, diabetes, and dyslipidemia 4 . Lifestyle factors, including smoking and plasma lipid levels, are also involved in the development of RVO 5 . The pathological mechanisms of RVO are gradually being recognized, yet clinical prevention and exploration of risk factors are still not fully revealed.…”