Hansen Aleksander L, Andersen Mette K, Engelhard Leonie M, Brøns Charlotte, Hansen Torben, Nielsen Jens S, Vestergaard Peter, Højlund Kurt, Jessen Niels, Olsen Michael H, Thomsen Reimar W, Vaag Allan
Steno Diabetes Center Copenhagen, Herlev, Denmark.
Department of Clinical Epidemiology, Aarhus University Hospital, and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Diabetes Obes Metab. 2025 Apr;27(4):2002-2011. doi: 10.1111/dom.16193. Epub 2025 Jan 8.
TCF7L2 rs7903146 is the most impactful single genetic risk variant for type 2 diabetes. However, its role on disease progression, complications and mortality among people with type 2 diabetes at diagnosis remains unclear.
We assessed the per allele impact of the rs7903146 T-allele on clinical characteristics and complication risk in 9231 individuals with type 2 diabetes at diagnosis and over a 10-year follow-up period. Log-binomial and robust Poisson regression analyses were used to estimate prevalence ratios for clinical characteristics and macro- and microvascular complications at diabetes onset, while Cox regression was applied to estimate the risk of complications post-diagnosis. Analyses were adjusted for sex, calendar year at birth, age at enrollment and diabetes duration.
The per T-allele impact was associated with 0.6 kg/m (95% CI: 0.4, 0.8) lower BMI, 1.4 cm (95% CI: 1.0, 1.8) smaller waist circumference, 5.6% (95% CI: 4.2, 7.0) lower insulin secretion and 5.0% (95% CI: 3.3, 6.7) higher insulin sensitivity. Over 10 years, the per T-allele impact was associated with lower risks for major adverse cardiovascular events (0.87 [95% CI 0.79, 0.95]), myocardial infarction (0.82 [95% CI: 0.72, 0.93]) and heart failure (0.85 [95% CI 0.73, 1.00]), with no significant impact on microvascular complications.
The TCF7L2 variant is associated with less obesity, lower insulin secretion and higher insulin action at diabetes onset, and decreased risk of cardiovascular events following type 2 diabetes onset.
TCF7L2基因的rs7903146位点是2型糖尿病最具影响力的单基因风险变异。然而，其在2型糖尿病确诊患者的疾病进展、并发症及死亡率方面所起的作用仍不明确。
我们评估了rs7903146位点的T等位基因对9231例确诊2型糖尿病患者临床特征及并发症风险的单等位基因影响，并进行了为期10年的随访。采用对数二项式回归和稳健泊松回归分析来估计糖尿病发病时临床特征以及大血管和微血管并发症的患病率比，同时应用Cox回归分析来估计确诊后并发症的风险。分析对性别、出生年份、入组年龄和糖尿病病程进行了校正。
每一个T等位基因的影响与体重指数降低0.6kg/m²（95%置信区间：0.4，0.8）、腰围减小1.4cm（95%置信区间：1.0，1.8）、胰岛素分泌降低5.6%（95%置信区间：4.2，7.0）以及胰岛素敏感性提高5.0%（95%置信区间：3.3，6.7）相关。在10年期间，每一个T等位基因的影响与主要不良心血管事件风险降低（0.87 [95%置信区间0.79，0.95]）、心肌梗死风险降低（0.82 [95%置信区间：0.72，0.93]）和心力衰竭风险降低（0.85 [95%置信区间0.73，1.00]）相关，对微血管并发症无显著影响。
TCF7L2基因变异与糖尿病发病时肥胖程度较低、胰岛素分泌减少和胰岛素作用增强相关，且2型糖尿病发病后心血管事件风险降低。
