Research Division, Joslin Diabetes Center, Boston, MA.
Department of Medicine, Harvard Medical School, Boston, MA.
Diabetes Care. 2018 Feb;41(2):348-355. doi: 10.2337/dc17-1638. Epub 2017 Nov 28.
A genome-wide association study in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial identified two markers (rs57922 and rs9299870) that were significantly associated with cardiovascular mortality during intensive glycemic control and could potentially be used, when combined into a genetic risk score (GRS), to identify patients with diabetes likely to derive benefit from intensive control rather than harm. The aim of this study was to gain insights into the pathways involved in the modulatory effect of these variants.
Fasting levels of 65 biomarkers were measured at baseline and at 12 months of follow-up in the ACCORD-Memory in Diabetes (ACCORD-MIND) MRI substudy ( = 562). Using linear regression models, we tested the association of the GRS with baseline and 12-month biomarker levels, and with their difference (Δ), among white subjects, with genotype data ( = 351) stratified by intervention arm.
A significant association was observed between GRS and ΔGLP-1 (glucagon-like peptide 1, active) in the intensive arm ( = 3 × 10). This effect was driven by rs57922 ( = 5 × 10). C/C homozygotes, who had been found to derive cardiovascular benefits from intensive treatment, showed a 22% increase in GLP-1 levels during follow-up. By contrast, T/T homozygotes, who had been found to experience increased cardiac mortality with intensive treatment, showed a 28% reduction in GLP-1 levels. No association between ΔGLP-1 and GRS or rs57922 was observed in the standard treatment arm.
Differences in GLP-1 axis activation may mediate the modulatory effect of variant rs57922 on the cardiovascular response to intensive glycemic control. These findings highlight the importance of GLP-1 as a cardioprotective factor.
在“行动控制心血管风险糖尿病（ACCORD）试验”中进行的全基因组关联研究鉴定出与强化血糖控制期间心血管死亡率显著相关的两个标记物（rs57922 和 rs9299870），并且当它们组合成遗传风险评分（GRS）时，可潜在用于识别可能从强化控制中获益而不是受到伤害的糖尿病患者。本研究旨在深入了解这些变异体的调节作用所涉及的途径。
在 ACCORD-Memory in Diabetes（ACCORD-MIND）MRI 子研究（n = 562）中，在基线和 12 个月随访时测量了 65 种生物标志物的空腹水平。使用线性回归模型，我们在白人受试者中测试了 GRS 与基线和 12 个月生物标志物水平的关联，以及与干预组分层的基因型数据（n = 351）的差异（Δ）。
在强化组中观察到 GRS 与 ΔGLP-1（胰高血糖素样肽 1，活性）之间存在显著关联（n = 3 × 10）。这种作用是由 rs57922 驱动的（n = 5 × 10）。已经发现 C/C 纯合子从强化治疗中获得心血管益处，在随访期间 GLP-1 水平增加了 22%。相比之下，已经发现 T/T 纯合子从强化治疗中经历了心脏死亡率的增加，GLP-1 水平降低了 28%。在标准治疗组中未观察到 ΔGLP-1 与 GRS 或 rs57922 之间的关联。
GLP-1 轴激活的差异可能介导了变异 rs57922 对强化血糖控制的心血管反应的调节作用。这些发现强调了 GLP-1 作为心脏保护因子的重要性。
