Genetic Evidence for a Causal Role of Obesity in Diabetic Kidney Disease.
Genetic Evidence for a Causal Role of Obesity in Diabetic Kidney Disease.
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作者：
Todd JN;Dahlström EH;Salem RM;Sandholm N;Forsblom C;FinnDiane Study Group;McKnight AJ;Maxwell AP;Brennan E;Sadlier D;Godson C;Groop PH;Hirschhorn JN;Florez JC
肥胖被认为是糖尿病肾病（DKD）的独立危险因素，但从观察数据中建立因果关系是有问题的。我们的目的是使用孟德尔随机化来测试肥胖是否与DKD有因果关系，孟德尔随机化利用了减数分裂期间基因的随机分配。在6，049例1型糖尿病受试者中，我们使用由32个经验证的BMI位点组成的加权遗传风险评分（GRS）作为工具来测试BMI与大量白蛋白尿、终末期肾病（ESRD）或DKD（定义为大量白蛋白尿或ESRD的存在）的关系。我们将这些结果与横截面和纵向观察相关性进行了比较。纵向分析表明，随着时间的推移，BMI与大量白蛋白尿、ESRD或DKD的发展呈U形关系。横断面观察分析显示与总体DKD、大量白蛋白尿的几率较高（BMI每增加1 kg/m2，比值比[OR] 1.05，95% CI 1.03-1.07，P < 0.001）和ESRD的几率较低（OR 0.95，95% CI 0.93-0.97，P < 0.001）无关。孟德尔随机化分析显示，BMI增加1 kg/m2，导致大量白蛋白尿（OR 1.28，95% CI 1.11-1.45，P = 0.001）、ESRD（OR 1.43，95% CI 1.20-1.72，P < 0.001）和DKD（OR 1.33，95% CI 1.17-1.51，P < 0.001）风险增加。我们的研究结果为肥胖和1型糖尿病DKD之间的因果关系提供了遗传学证据。随着肥胖患病率的上升，这一发现预测DKD患病率会增加，除非采取干预措施。
Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD), but establishing causality from observational data is problematic. We aimed to test whether obesity is causally related to DKD using Mendelian randomization, which exploits the random assortment of genes during meiosis. In 6,049 subjects with type 1 diabetes, we used a weighted genetic risk score (GRS) comprised of 32 validated BMI loci as an instrument to test the relationship of BMI with macroalbuminuria, end-stage renal disease (ESRD), or DKD defined as presence of macroalbuminuria or ESRD. We compared these results with cross-sectional and longitudinal observational associations. Longitudinal analysis demonstrated a U-shaped relationship of BMI with development of macroalbuminuria, ESRD, or DKD over time. Cross-sectional observational analysis showed no association with overall DKD, higher odds of macroalbuminuria (for every 1 kg/m2 higher BMI, odds ratio [OR] 1.05, 95% CI 1.03–1.07, P < 0.001), and lower odds of ESRD (OR 0.95, 95% CI 0.93–0.97, P < 0.001). Mendelian randomization analysis showed a 1 kg/m2 higher BMI conferring an increased risk in macroalbuminuria (OR 1.28, 95% CI 1.11–1.45, P = 0.001), ESRD (OR 1.43, 95% CI 1.20–1.72, P < 0.001), and DKD (OR 1.33, 95% CI 1.17–1.51, P < 0.001). Our results provide genetic evidence for a causal link between obesity and DKD in type 1 diabetes. As obesity prevalence rises, this finding predicts an increase in DKD prevalence unless intervention should occur.