AIMS/HYPOTHESIS Reactive α-dicarbonyl compounds are major precursors of AGEs and may lead to glycation of circulating and/or cell-associated complement regulators. Glycation of complement regulatory proteins can influence their capacity to inhibit complement activation. We investigated, in a human cohort, whether greater dicarbonyl stress was associated with more complement activation. METHODS Circulating concentrations of dicarbonyl stress markers, i.e. α-dicarbonyls (methylglyoxal [MGO], glyoxal [GO] and 3-deoxyglucosone [3-DG]), and free AGEs (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL] and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine [MG-H1]), and protein-bound AGEs (CML, CEL, pentosidine), as well as the complement activation products C3a and soluble C5b-9 (sC5b-9), were measured in 530 participants (59.5 ± 7.0 years [mean ± SD], 61% men) of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Multiple linear regression analyses were used to investigate the associations between dicarbonyl stress (standardised) and complement activation (standardised) with adjustment of potential confounders, including age, sex, lifestyle, use of medication and markers of obesity. In addition, the associations of two potentially functional polymorphisms (rs1049346, rs2736654) in the gene encoding glyoxalase 1 (GLO1), the rate-limiting detoxifying enzyme for MGO, with C3a and sC5b-9 (all standardized) were evaluated. RESULTS After adjustment for potential confounders, plasma concentration of the dicarbonyl GO was inversely associated with sC5b-9 (β -0.12 [95% CI -0.21, -0.02]) and the protein-bound AGE CEL was inversely associated with C3a (-0.17 [-0.25, -0.08]). In contrast, the protein-bound AGE pentosidine was positively associated with sC5b-9 (0.15 [0.05, 0.24]). No associations were observed for other α-dicarbonyls and other free or protein-bound AGEs with C3a or sC5b-9. Individuals with the AG and AA genotype of rs1049346 had, on average, 0.32 and 0.40 SD lower plasma concentrations of sC5b-9 than those with the GG genotype, while concentrations of C3a did not differ significantly between rs1049346 genotypes. GLO1 rs2736654 was not associated with either C3a or sC5b-9. CONCLUSIONS/INTERPRETATION Plasma concentrations of dicarbonyl stress markers showed distinct associations with complement activation products: some of them were inversely associated with either C3a or sC5b-9, while protein-bound pentosidine was consistently and positively associated with sC5b-9. This suggests different biological relationships of individual dicarbonyl stress markers with complement activation.

中文翻译：

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二羰基应力与补体激活的关联：CODAM研究。

目的/假设反应性α-二羰基化合物是AGEs的主要前体，可能导致循环和/或细胞相关补体调节剂糖化。补体调节蛋白的糖基化可影响其抑制补体激活的能力。我们在一个人类队列中研究了更大的二羰基应激是否与更多的补体激活有关。方法循环浓度的二羰基应激标志物，即α-二羰基（甲基乙二醛[MGO]，乙二醛[GO]和3-脱氧葡糖酮[3-DG]）和游离AGEs（Nε-（羧甲基）赖氨酸[CML]，Nε-（羧乙基）赖氨酸[CEL]和Nδ-（5-氢-5-甲基-4-咪唑啉-2-基）-鸟氨酸[MG-H1]），以及蛋白结合的AGEs（CML，CEL，戊糖苷）在530名参与者中（59.5±7）测量了补体激活产物C3a和可溶性C5b-9（sC5b-9）。0年[平均±标准差]，男性占61％）进行了关于马斯特里赫特糖尿病和动脉粥样硬化研究（CODAM）的研究。多元线性回归分析用于研究二羰基应激（标准化）和补体激活（标准化）之间的关联，并调整潜在混杂因素，包括年龄，性别，生活方式，药物使用和肥胖症标志物。此外，评估了编码乙二醛酶1（GLO1）的基因（MGO的限速解毒酶）中两个潜在功能性多态性（rs1049346，rs2736654）与C3a和sC5b-9（均已标准化）的关联。结果调整潜在混杂因素后，二羰基GO的血浆浓度与sC5b-9呈负相关（β-0.12 [95％CI -0.21，-0.02]），与蛋白质结合的AGE CEL与C3a呈负相关（-0.17） [-0.25，-0.08]）。相反，与蛋白质结合的AGE Pentosidine与sC5b-9正相关（0.15 [0.05，0.24]）。没有观察到其他α-二羰基和其他游离或蛋白结合的AGEs与C3a或sC5b-9的关联。具有rs1049346的AG和AA基因型的个体的sC5b-9血浆浓度平均比具有GG基因型的个体低0.32和0.40 SD，而C3a的浓度在rs1049346基因型之间没有显着差异。GLO1 rs2736654与C3a或sC5b-9没有关联。结论/解释血浆中的二羰基应激标志物浓度与补体激活产物有明显的联系：其中一些与C3a或sC5b-9呈负相关，而与蛋白质结合的戊糖苷与sC5b-9呈正相关。