Xue Can Can, Li Hengtong, Yu Marco, Chong Crystal Chun Yuen, Fan Qiao, Tham Yih-Chung, Cheung Chui Ming Gemmy, Wong Tien Yin, Chew Emily Y, Cheng Ching-Yu
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Republic of Singapore.
Centre for Innovation and Precision Eye Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
Ophthalmology. 2025 May;132(5):598-609. doi: 10.1016/j.ophtha.2024.12.005. Epub 2024 Dec 9.
Epidemiologic studies and clinical trials have reported inconsistent findings regarding omega-3 fatty acids' protective role in age-related macular degeneration (AMD). We investigated their association in a prospective cohort and examined causality using Mendelian randomization (MR) analyses.
Prospective cohort study and 2-sample MR analyses.
The cohort included 258 350 AMD-free individuals of European descent from the UK Biobank. Mendelian randomization analyses used genome-wide association study data on plasma omega-3 and docosahexaenoic acid (DHA) (UK Biobank, n = 115 006) and AMD (dry, wet, and any; FinnGen, n = 208 690-209 122).
Cox regression assessed the association between plasma omega-3 and DHA levels and AMD incidence, adjusting for systemic covariates and AMD polygenetic risk score (PRS). Interaction effects of AMD genetic risk (PRS, complement factor H and age-related maculopathy susceptibility 2 genotypes), and plasma omega-3 and DHA levels were tested. For MR analyses, we used random-effect inverse-variance weighted model as primary, with 5 sensitivity models. Causality was considered significant if P < 0.05 in the primary model and at least 2 sensitivity models.
Risk of AMD.
Over 12.9 years, 5068 people (1.9%) demonstrated AMD. Higher plasma levels (in millimoles per liter) of omega-3 (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.72-0.95; P = 0.006) and DHA (HR, 0.65; 95% CI, 0.44-0.96; P = 0.029) were associated with lower risk of receiving an AMD diagnosis. Mendelian randomization showed genetic predisposition to higher plasma omega-3 levels reduced the risk of dry AMD (odds ratio [OR], 0.83; 95% CI, 0.73-0.96; P = 0.010), wet AMD (OR, 0.76; 95% CI, 0.65-0.88; P < 0.001), and any AMD (OR, 0.82; 95% CI, 0.74-0.92; P < 0.001). Similar results were found for plasma DHA levels (wet AMD:OR, 0.79; 95% CI, 0.65-0.96; P = 0.017; any AMD: OR, 0.84; 95% CI, 0.72-0.98; P = 0.030). No significant interaction was found between omega-3 and DHA levels and AMD genetic risk (all P > 0.05).
Both the prospective and MR analyses suggest omega-3 and DHA may protect against AMD, supporting the need for further clinical trials to test their effectiveness in AMD prevention and treatment.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
流行病学研究和临床试验关于ω-3脂肪酸在年龄相关性黄斑变性（AMD）中的保护作用报告了不一致的结果。我们在一项前瞻性队列研究中调查了它们之间的关联，并使用孟德尔随机化（MR）分析来检验因果关系。
前瞻性队列研究和两样本MR分析。
该队列包括来自英国生物银行的258350名无AMD的欧洲血统个体。孟德尔随机化分析使用了关于血浆ω-3和二十二碳六烯酸（DHA）的全基因组关联研究数据（英国生物银行，n = 115006）以及AMD（干性、湿性和任何类型；芬兰基因库，n = 208690 - 209122）的数据。
Cox回归评估血浆ω-3和DHA水平与AMD发病率之间的关联，并对全身协变量和AMD多基因风险评分（PRS）进行调整。测试了AMD遗传风险（PRS、补体因子H和年龄相关性黄斑病变易感性2基因型）与血浆ω-3和DHA水平的交互作用。对于MR分析，我们使用随机效应逆方差加权模型作为主要模型，并使用5种敏感性模型。如果在主要模型和至少2种敏感性模型中P < 0.05，则认为因果关系显著。
AMD风险。
在12.9年的时间里，5068人（1.9%）出现了AMD。较高的血浆ω-3水平（每升毫摩尔数）（风险比[HR]，0.80；95%置信区间[CI]，0.72 - 0.95；P = 0.006）和DHA水平（HR，0.65；95% CI，0.44 - 0.96；P = 0.029）与较低的AMD诊断风险相关。孟德尔随机化显示，较高血浆ω-3水平的遗传易感性降低了干性AMD的风险（优势比[OR]，0.83；95% CI，0.73 - 0.96；P = 0.010）、湿性AMD的风险（OR，0.76；95% CI，0.65 - 0.88；P < 0.001）以及任何类型AMD的风险（OR，0.82；95% CI，0.74 - 0.92；P < 0.001）。血浆DHA水平也有类似结果（湿性AMD：OR，0.79；95% CI，0.65 - 0.96；P = 0.017；任何类型AMD：OR，0.84；95% CI，0.72 - 0.98；P = 0.030）。未发现ω-3和DHA水平与AMD遗传风险之间存在显著交互作用（所有P > 0.05）。
前瞻性研究和MR分析均表明，ω-3和DHA可能对AMD具有保护作用，这支持了开展进一步临床试验以测试其在AMD预防和治疗中的有效性的必要性。
在本文末尾的脚注和披露中可能会发现专有或商业披露信息。
