γ-谷氨酰转移酶水平、糖尿病前期和 2 型糖尿病：一项孟德尔随机研究。
Gamma-glutamyltransferase levels, prediabetes and type 2 diabetes: a Mendelian randomization study.
机构信息
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
出版信息
Int J Epidemiol. 2017 Oct 1;46(5):1400-1409. doi: 10.1093/ije/dyx006.
BACKGROUND
High levels of serum gamma-glutamyltransferase (GGT) are associated with increased risk of prediabetes and type 2 diabetes in observational studies. It is unclear whether this relationship is causal, arises from residual confounding or is a consequence of reverse causation.
METHODS
We used data from a prospective population-based cohort study, compromising 8611 individuals without diabetes at baseline. Cox proportional hazard models were used to study the association between serum GGT levels and incident prediabetes and diabetes. A Mendelian randomization (MR) study was performed using a genetic risk score consisting of 26 GGT-related variants, based on a genome-wide association study (GWAS) on liver enzymes. Association with diabetes and glycaemic traits were investigated within the Rotterdam Study and large-scale GWAS.
RESULTS
During follow-up, 1125 cases of prediabetes (mean follow-up 5.7 years) and 811 cases of type 2 diabetes (6.9 years) were ascertained. The predicted hazard ratios per standard deviation (SD) change in GGT levels in the multivariable model were 1.10 for prediabetes [95% confidence interval (CI): 1.02-1.19] and 1.19 for type 2 diabetes (95% CI: 1.10-1.30). The genetic risk score associated with increased GGT levels (beta per SD log GGT = 0.41, 95% CI: 0.35-0.47), explaining 3.5% of the observed variation in GGT. MR analysis did not provide evidence for a causal role of GGT, with a causal relative risk for prediabetes and type 2 diabetes per SD of log GGT of 0.97 (95% CI: 0.91-1.04) and 0.96 (95% CI: 0.89-1.04), respectively. Multiple instrumental analysis using genetic associations with type 2 diabetes and glycaemic traits from previous GWA studies detected no causal effect of GGT.
CONCLUSIONS
MR analyses did not support a causal role of GGT on the risk of prediabetes or diabetes. The association of GGT with diabetes in observational studies is likely to be driven by reverse causation or confounding bias. As such, therapeutics targeted at lowering GGT levels are unlikely to be effective in preventing diabetes.
背景
在观察性研究中，血清γ-谷氨酰转移酶（GGT）水平升高与前驱糖尿病和 2 型糖尿病的风险增加相关。目前尚不清楚这种关系是因果关系、源于残余混杂因素还是反向因果关系的结果。
方法
我们使用了一项前瞻性人群队列研究的数据，该研究纳入了 8611 名基线时无糖尿病的个体。采用 Cox 比例风险模型研究血清 GGT 水平与前驱糖尿病和糖尿病发病的关系。使用基于肝脏酶全基因组关联研究（GWAS）的 26 个与 GGT 相关的变异的遗传风险评分进行孟德尔随机化（MR）研究。在鹿特丹研究和大规模 GWAS 中，研究了与糖尿病和血糖特征的关联。
结果
在随访期间，确定了 1125 例前驱糖尿病病例（平均随访 5.7 年）和 811 例 2 型糖尿病病例（6.9 年）。多变量模型中 GGT 水平每标准差（SD）变化的预测风险比为 1.10（95%可信区间：1.02-1.19）用于前驱糖尿病，1.19（95%可信区间：1.10-1.30）用于 2 型糖尿病。与 GGT 水平升高相关的遗传风险评分（每个 SD log GGT 的β值为 0.41，95%可信区间：0.35-0.47），解释了 GGT 观察到的变异的 3.5%。MR 分析并未提供 GGT 具有因果作用的证据，SD 对数 GGT 每增加一个单位，前驱糖尿病和 2 型糖尿病的相对风险分别为 0.97（95%可信区间：0.91-1.04）和 0.96（95%可信区间：0.89-1.04）。使用来自先前 GWAS 研究的与 2 型糖尿病和血糖特征相关的遗传关联进行的多重工具分析并未检测到 GGT 的因果作用。
结论
MR 分析不支持 GGT 对前驱糖尿病或糖尿病风险的因果作用。在观察性研究中，GGT 与糖尿病的关联可能是由反向因果关系或混杂偏倚驱动的。因此，针对降低 GGT 水平的治疗方法不太可能有效预防糖尿病。
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