Massachusetts General Hospital and Harvard Medical School, Boston, and Arthritis Research Canada, Vancouver, British Columbia, Canada.
Brigham and Women's Hospital, Boston, Massachusetts.
Arthritis Care Res (Hoboken). 2024 Dec;76(12):1666-1674. doi: 10.1002/acr.25420. Epub 2024 Oct 16.
Our objective was to prospectively investigate prediagnostic population-based metabolome for risk of hospitalized gout (ie, most accurate, severe, and costly cases), accounting for serum urate.
We conducted prediagnostic metabolome-wide analyses among 249,677 UK Biobank participants with nuclear magnetic resonance metabolomic profiling (N = 168 metabolites, including eight amino acids) from baseline blood samples (2006-2010) without a history of gout. We calculated multivariable hazard ratios (HRs) for hospitalized incident gout, before and after adjusting for serum urate levels; we included patients with nonhospitalized incident gout in a sensitivity analysis. Potential causal effects were evaluated with two-sample Mendelian randomization.
Correcting for multiple testing, 107 metabolites were associated with incidence of hospitalized gout (n = 2,735) before urate adjustment, including glycine and glutamine (glutamine HR 0.64, 95% confidence interval [CI] 0.54-0.75, P = 8.3 × 10; glycine HR 0.69, 95% CI 0.61-0.78, P = 3.3 × 10 between extreme quintiles), and glycoprotein acetyls (HR 2.48, 95% CI 2.15-2.87, P = 1.96 × 10). Associations remained significant and directionally consistent following urate adjustment (HR 0.83, 95% CI 0.70-0.98; HR 0.86, 95% CI 0.76-0.98; HR 1.41, 95% CI 1.21-1.63 between extreme quintiles), respectively; corresponding HRs per SD were 0.91 (95% CI 0.86-0.97), 0.94 (95% CI 0.91-0.98), and 1.10 (95% CI 1.06-1.14). Findings persisted when including patients with nonhospitalized incident gout. Mendelian randomization corroborated their potential causal role on hyperuricemia or gout risk; with change in urate levels of -0.05 mg/dL (95% CI -0.08 to -0.01) and -0.12 mg/dL (95% CI -0.22 to -0.03) per SD of glycine and glutamine, respectively, and odds ratios of 0.94 (95% CI 0.88-1.00) and 0.81 (95% CI 0.67-0.97) for gout.
These prospective findings with causal implications could lead to biomarker-based risk prediction and potential supplementation-based interventions with glycine or glutamine.
本研究旨在前瞻性地研究基于人群的代谢组学在预测住院痛风（即最准确、最严重和最昂贵的病例）中的作用，同时考虑血清尿酸水平。
我们对来自英国生物库的 249677 名参与者进行了基于人群的代谢组学全谱分析，这些参与者在基线血液样本（2006-2010 年）中进行了核磁共振代谢组学分析（N=168 种代谢物，包括 8 种氨基酸），且无痛风病史。我们计算了多变量风险比（HR），用于预测住院痛风的发生，在调整血清尿酸水平前后均进行了分析；我们在敏感性分析中纳入了非住院痛风患者。采用两样本孟德尔随机化评估潜在的因果效应。
在未调整尿酸的情况下，107 种代谢物与住院痛风（n=2735）的发生相关，包括甘氨酸和谷氨酰胺（谷氨酰胺 HR 0.64，95%置信区间[CI]0.54-0.75，P=8.3×10-4；甘氨酸 HR 0.69，95%CI 0.61-0.78，P=3.3×10-5，位于极端五分位数之间）和糖蛋白乙酰基（HR 2.48，95%CI 2.15-2.87，P=1.96×10-3）。在调整尿酸后，这些关联仍然显著且方向一致（HR 0.83，95%CI 0.70-0.98；HR 0.86，95%CI 0.76-0.98；HR 1.41，95%CI 1.21-1.63，位于极端五分位数之间）；相应的 SD 每增加 1 个单位，HR 分别为 0.91（95%CI 0.86-0.97）、0.94（95%CI 0.91-0.98）和 1.10（95%CI 1.06-1.14）。当纳入非住院痛风患者时，结果仍然存在。孟德尔随机化证实了它们在高尿酸血症或痛风风险方面的潜在因果作用；甘氨酸和谷氨酰胺的尿酸水平分别降低 0.05mg/dL（95%CI 0.08-0.01）和 0.12mg/dL（95%CI 0.22-0.03），甘氨酸和谷氨酰胺的比值分别为 0.94（95%CI 0.88-1.00）和 0.81（95%CI 0.67-0.97）。
这些具有因果关系的前瞻性发现可能会导致基于生物标志物的风险预测和潜在的基于补充剂的甘氨酸或谷氨酰胺干预痛风。
