OBJECTIVE Telomere shortening and DNA oxidation are associated with premature vascular aging, which may be involved in lower-extremity amputation (LEA). We sought to investigate whether leukocyte telomere length (LTL) and plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation, were associated with LEA in subjects with type 1 diabetes at high vascular risk. RESEARCH DESIGN AND METHODS LTL (quantitative PCR) and plasma 8-OHdG concentrations (immunoassay method) were assessed at baseline in the GENEDIAB (Génétique de la Néphropathie Diabétique) type 1 diabetes cohort. Logistic and Cox proportional hazards regression models were fitted to estimate odds ratio (OR) (at baseline) and hazard ratio (HR) (during follow-up), with related 95% CI, by increasing biomarker tertiles (T1, T2, T3). RESULTS Among 478 participants (56% male and mean ± SD age 45 ± 12 years and diabetes duration 29 ± 10 years), 84 patients had LEA at baseline. Baseline history of LEA was associated with shorter LTL (OR for T2 vs. T1 0.62 [95% CI 0.32-1.22] and for T3 vs. T1 0.41 [0.20-0.84]) but not with plasma 8-OHdG (1.16 [0.56-2.39] and 1.24 [0.61-2.55], respectively). New cases of LEA occurred in 34 (12.3%) participants during 10-year follow-up. LTL were shorter (HR T2 vs. T1 0.25 [95% CI 0.08-0.67] and T3 vs. T1 0.29 [0.10-0.77]) and plasma 8-OHdG higher (2.20 [0.76-7.35] and 3.11 [1.07-10.32]) in participants who developed LEA during follow-up compared with others. No significant interaction was observed between biomarkers on their association with LEA. CONCLUSIONS We report the first independent association between LTL shortening and excess risk of LEA in type 1 diabetes. High plasma 8-OHdG was also associated with incident LEA but partly dependent on cofounding variables.

中文翻译：

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长期存在的1型糖尿病患者的白细胞端粒长度，DNA氧化和下肢截肢的风险。

目的端粒缩短和DNA氧化与血管早衰相关，可能与下肢截肢（LEA）有关。我们试图调查在高血管风险的1型糖尿病患者中，白细胞端粒长度（LTL）和血浆8-羟基-2'-脱氧鸟苷（8-OHdG）是DNA氧化的生物标志物是否与LEA相关。研究设计和方法在GENEDIAB（Génétiquede laNéphropathieDiabétique）1型糖尿病队列中，在基线时评估了LTL（定量PCR）和血浆8-OHdG浓度（免疫测定方法）。通过增加生物标志物三分位数（T1，T2，T3）拟合Logistic和Cox比例风险回归模型以估计比值比（OR）（处于基线状态）和风险比（HR）（随访期间）以及相关的95％CI 。结果在478名参与者中（56％为男性，平均±SD年龄为45±12岁，糖尿病病程为29±10年），有84名患者在基线时有LEA。LEA的基线历史与较短的LTL相关（T2与T1的OR为0.62 [95％CI 0.32-1.22]，T3与T1的OR为0.41 [0.20-0.84]），但与血浆8-OHdG无关（1.16 [0.56-分别为[2.39]和1.24 [0.61-2.55]）。在10年的随访期间，有34位（12.3％）参与者发生了新的LEA病例。LTL较短（HR T2与T1 0.25 [95％CI 0.08-0.67]和T3与T1 0.29 [0.10-0.77]），血浆8-OHdG较高（2.20 [0.76-7.35]和3.11 [1.07-10.32]） ）与其他人相比，在随访过程中发展了LEA的参与者。生物标志物与LEA的相关性之间未观察到明显的相互作用。结论我们报告了LTL缩短与1型糖尿病LEA过多风险之间的第一个独立关联。高血浆8-OHdG也与入射LEA相关，但部分取决于共创变量。