Serum C-reactive protein (CRP), an important inflammatory marker, has been associated with age-related macular degeneration (AMD) in observational studies; however, the findings are inconsistent. It remains unclear whether the association between circulating CRP levels and AMD is causal. We used two-sample Mendelian randomization (MR) to evaluate the potential causal relationship between serum CRP levels and AMD risk. We derived genetic instruments for serum CRP levels in 418,642 participants of European ancestry from UK Biobank, and then conducted a genome-wide association study for 12,711 advanced AMD cases and 14,590 controls of European descent from the International AMD Genomics Consortium. Genetic variants which predicted elevated serum CRP levels were associated with advanced AMD (odds ratio [OR] for per standard deviation increase in serum CRP levels: 1.31, 95% confidence interval [CI]: 1.19-1.44, P = 5.2 × 10-8). The OR for the increase in advanced AMD risk when moving from low (< 3 mg/L) to high (> 3 mg/L) CRP levels is 1.29 (95% CI: 1.17-1.41). Our results were unchanged in sensitivity analyses using MR models which make different modelling assumptions. Our findings were broadly similar across the different forms of AMD (intermediate AMD, choroidal neovascularization, and geographic atrophy). We used multivariable MR to adjust for the effects of other potential AMD risk factors including smoking, body mass index, blood pressure and cholesterol; this did not alter our findings. Our study provides strong genetic evidence that higher circulating CRP levels lead to increases in risk for all forms of AMD. These findings highlight the potential utility for using circulating CRP as a biomarker in future trials aimed at modulating AMD risk via systemic therapies.

中文翻译：

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使用孟德尔随机法评估血清C反应蛋白水平与年龄相关性黄斑变性之间的因果关系。

血清C反应蛋白（CRP）是一种重要的炎症标志物，在观察研究中已与年龄相关性黄斑变性（AMD）相关。但是，结果不一致。目前尚不清楚循环CRP水平与AMD之间的关联是否是因果关系。我们使用两次样本孟德尔随机（MR）评估血清CRP水平和AMD风险之间的潜在因果关系。我们从UK Biobank衍生了418,642名欧洲血统的血清CRP水平的遗传仪器，然后对国际AMD Genomics Consortium的12,711例晚期AMD病例和14,590例欧洲血统对照进行了全基因组关联研究。预测血清CRP水平升高的遗传变异与晚期AMD相关（血清CRP水平每标准偏差增加的比值比[OR]：1.31，95％置信区间[CI]：1.19-1.44，P = 5.2×10-8 ）。从低（<3 mg / L）到高（> 3 mg / L）CRP水平时，晚期AMD风险增加的OR为1.29（95％CI：1.17-1.41）。我们的结果在使用MR模型的敏感性分析中没有变化，而MR模型做出了不同的模型假设。我们在不同形式的AMD（中间AMD，脉络膜新血管形成和地理萎缩）中的发现大致相似。我们使用多变量MR来调整其他潜在的AMD危险因素的影响，包括吸烟，体重指数，血压和胆固醇。这并没有改变我们的发现。我们的研究提供了强有力的遗传学证据，表明较高的循环CRP水平会导致各种形式的AMD风险增加。这些发现突显了在未来旨在通过系统疗法调节AMD风险的试验中，将循环CRP用作生物标记物的潜在实用性。