背景:脂质代谢失衡与AMD的发展有关,但AMD与血浆脂肪酸(FAs)之间的因果关系仍存在争议。使用双样本孟德尔随机化(MR)方法,我们试图评估特定FA血浆水平对不同AMD亚型风险的影响.
方法:我们分析了来自英国生物库的115,006个欧洲后代个体的循环FAs的全基因组关联数据。这些数据用于双样品MR框架中,以评估循环FA在发展湿性和干性AMD中的潜在作用。进行了敏感性分析,以确保我们的研究结果的稳健性。进行了其他多变量和基因座特异性MR分析,以评估FA对AMD亚型的直接影响,最大限度地减少脂蛋白相关性状和甘油三酯的偏差。
结果:孟德尔随机化显示,omega-3与降低的湿性(OR0.78,95CI0.66-0.92)和干性AMD(0.85,0.74-0.97)风险相关。对AMD有保护作用。值得注意的是,omega-6与omega-3的比值对湿性AMD(1.27,1.03-1.56)和干性AMD(1.18,1.02-1.37)均显示出潜在的因果效应.多变量MR表明,在HDL调节后,omega-3,omega-6与omega-3比率对湿性AMD的因果关系仍然存在。LDL和甘油三酯,尽管证据强度略有下降。与omega-3相关的基因座特异性MR(FADS1,0.89,0.82-0.98;FADS2,0.88,0.81-0.96)和omega-6与omega-3的比率(FADS1,1.10,1.02-1.20;FADS2,1.11,1.03-1.20)表明这些因素对湿性AMD的因果关系。
结论:血浆FA浓度与AMD之间的关系,提示omega-3和omega-6与omega-3比率在湿性AMD中的潜在因果作用。这些结果强调了从MR角度来看不平衡的循环ω-3和ω-6FA比率对AMD病理生理学的影响。
BACKGROUND: An imbalance in lipid metabolism has been linked to the development of AMD, but the causal relationship between AMD and plasma fatty acids (FAs) remains controversial. Using a two-sample Mendelian randomization (MR) approach, we sought to evaluate the impact of specific FA plasma levels on the risk of different AMD subtypes.
METHODS: We analysed genome-wide association data of circulating FAs from 115,006 European-descended individuals in the UK Biobank. These data were used in a two-sample MR framework to assess the potential role of circulating FAs in developing wet and dry AMD. Sensitivity analyses were conducted to ensure the robustness of our findings. Additional multivariable and locus-specific MR analyses were conducted to evaluate direct effects of FA on AMD subtypes, minimizing biases from lipoprotein-related traits and triglycerides.
RESULTS: Mendelian randomization revealed associations of omega-3 was associated with decreased wet (OR 0.78, 95%CI 0.66-0.92) and dry AMD (0.85, 0.74-0.97) risk, showed a protective effect on AMD. Notably, the omega-6 to omega-3 ratio showed potential causal effects on both wet (1.27, 1.03-1.56) and dry AMD (1.18, 1.02-1.37). Multivariable MR suggested that the causal relationship of omega-3, omega-6 to omega-3 ratio on wet AMD persists after conditioning on HDL, LDL and triglycerides, albeit with slightly diminished evidence strength. Locus-specific MR linked to omega-3(FADS1, 0.89, 0.82-0.98; FADS2, 0.88, 0.81-0.96) and omega-6 to omega-3 ratio (FADS1, 1.10, 1.02-1.20; FADS2, 1.11, 1.03-1.20) suggests causal effects of these factors on wet AMD.
CONCLUSIONS: The associations between plasma FA concentrations and AMD, suggest potential causal role of omega-3, and the omega-6 to omega-3 ratio in wet AMD. These results underscore the impact of an imbalanced circulating omega-3 and omega-6 FA ratio on AMD pathophysiology from MR perspective.