CAUSAL RELATIONSHIP BETWEEN PLASMA LIPID LEVELS AND AGE-RELATED CATARACT: A TWO-SAMPLE MENDELIAN RANDOMIZATION STUDY

Abstract

Background: Observational studies have been inconsistent due to confounding factors and reverse causality. The relationship between plasma lipid levels and age-related cataract (ARC) remains controversial. Objective：We aim to investigate the causal relationship between plasma lipid levels and ARC through a two-sample Mendelian randomization (MR) study. Methods: We performed a two-step MR analysis using univariable and multivariable MR to discover the causality of plasma lipid levels and ARC. We obtained the statistics including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and ARC based on European-ancestry individuals from the genome-wide association studies (GWAS). In the first step, we performed univariable MR analysis for each exposure. 76, 42, and 64 independent single nucleotide polymorphisms (SNPs) respectively associated with HDL-C, LDL-C, and TG were extracted as instrumental variables (IVs). In the second step, we performed multivariable MR analysis for HDL-C, LDL-C, and TG. Multivariable MR analysis was also performed to exclude other confounding factors that interfered with the results. The results of the two-sample MR analysis were assessed separately by inverse variance weighted (IVW), weighted median (WME), MR-Egger regression, simple mode (SM), and weighted mode (WM). The heterogeneity test, pleiotropy test, scatter plots, forest plots, and leave-one-out plots were performed for the sensitivity analysis and visualization of MR results. Results: The IVW analysis method in the first step revealed that low HDL-C was causally associated with ARC (β=-0.001, OR=0.999, 95%CI=0.997-1.000, P=0.011). Meanwhile, the β-value of the other four MR methods was consistent with the result of the IVW method. There was no evidence of a causal association between LDL-C (β=-1.152×10^-5, OR=1.000, 95%CI=0.998-1.002, P=0.988) or TG (β=0.001, OR=1.001, 95%CI=1.000-1.002, P=0.234) and ARC. In the second step, multivariable MR analysis excluded the effect of confounders on the relationship. No significant heterogeneity or horizontal pleiotropy was found to affect the assessment of causality. Conclusions: Our univariable and multivariable MR analysis indicated that low HDL-C was associated with ARC, but did not provide evidence to support a causal association between LDL-C or TG and the risk of ARC in individuals of European ancestry. It is necessary to conduct more research to explain their association and potential pathogenesis in the future.