DataSheet_2_To explore association between gamma-glutamyl transferase and type 2 diabetes using a real-world study and mendelian randomization analysis.pdf

AimThe association between gamma-glutamyl transferase (GGT) and type 2 diabetes mellitus (T2DM) is controversial. In this study, we investigated the association between GGT and the risk of T2DM using real-world data, Mendelian randomization (MR) analysis, and literature mining.
MethodsA cross-sectional study enrolled 3,048 participants (>40 years) from a community in Northeastern China was conducted. A generalized additive model was used to examine the relation between GGT and T2DM. A two-sample MR was performed to investigate the causal effect of GGT (61,089 individuals, mostly of European ancestry) on T2DM (29,193 cases and 182,573 controls of European ancestry).
ResultsGGT was related to glucose metabolism indicators, such as fasting plasma glucose and glycosylated hemoglobin (P < 0.05). The odds ratios (ORs) [95% confidence interval (95% CI), P] for T2DM across the GGT categories (14–16, 17–20, 21–25, 26–35, ≥36) were 1.14 [(0.88-1.47), P = 0.330], 1.55 [(1.22-1.98), P < 0.001], 1.87 [(1.47-2.28), P < 0.001], 1.97 [(1.55-2.52), P < 0.001], and 2.29 [(1.78-2.94), P < 0.001] versus GGT ≤ 13 category after adjusting for potential confounding factors. A generalized additive model identified a non-linear correlation between GGT and T2DM and indicated that the risk of T2DM almost levelled out when GGT exceeded 34 IU/L. The MR analysis showed that the odds of having T2DM for a one-time increase in genetically determined GGT was 0.998 [(0.995-1.002), P = 0.34].
ConclusionsOur analysis of observational study suggested that GGT, its increment, within a certain range, is indicative of the development of T2DM. However, MR analysis provided no evidence that GGT is a linear causal factor of T2DM. Further investigation is required to determine if GGT exerts a non-linear causal effect on T2DM.

研究目的：γ-谷氨酰转移酶（gamma-glutamyl transferase, GGT）与2型糖尿病（type 2 diabetes mellitus, T2DM）之间的关联尚存争议。本研究通过真实世界数据、孟德尔随机化（Mendelian randomization, MR）分析及文献挖掘，探究GGT与T2DM发病风险的关联。
方法：本研究开展一项横断面研究，纳入中国东北地区某社区的3048名年龄大于40岁的参与者。采用广义相加模型分析GGT与T2DM的关联。同时开展两样本MR分析，以探究GGT（纳入61089名研究对象，多为欧洲血统）对T2DM的因果效应，该分析的研究对象包含29193例T2DM患者与182573名欧洲血统对照个体。
结果：GGT与空腹血糖、糖化血红蛋白等糖代谢指标显著相关（P<0.05）。在校正潜在混杂因素后，相较于GGT≤13 IU/L的参照组，不同GGT分层（14~16、17~20、21~25、26~35、≥36 IU/L）对应的T2DM比值比（odds ratios, ORs）[95%置信区间（95% confidence interval, 95% CI）, P值]分别为1.14 [(0.88~1.47), P=0.330]、1.55 [(1.22~1.98), P<0.001]、1.87 [(1.47~2.28), P<0.001]、1.97 [(1.55~2.52), P<0.001]及2.29 [(1.78~2.94), P<0.001]。广义相加模型分析显示GGT与T2DM存在非线性关联，且当GGT超过34 IU/L时，T2DM发病风险基本趋于平稳。MR分析结果显示，遗传决定的GGT水平每升高1个单位，发生T2DM的比值比为0.998 [(0.995~1.002), P=0.34]。
结论：本观察性研究分析结果提示，在一定范围内，GGT及其水平升高可提示T2DM的发生发展。但MR分析未发现GGT作为T2DM线性因果影响因素的相关证据。未来仍需进一步研究，以明确GGT是否对T2DM存在非线性因果效应。