2型糖尿病、糖尿病遗传评分与肾功能下降及蛋白尿风险：一项孟德尔随机化研究
Type 2 Diabetes, Diabetes Genetic Score and Risk of Decreased Renal Function and Albuminuria: A Mendelian Randomization Study.
作者信息
Xu Min, Bi Yufang, Huang Ya, Xie Lan, Hao Mingli, Zhao Zhiyun, Xu Yu, Lu Jieli, Chen Yuhong, Sun Yimin, Qi Lu, Wang Weiqing, Ning Guang
机构信息
State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai 200025, China.
Department of Biomedical Engineering, Medical Systems Biology Research Center, Tsinghua University School of Medicine, 18 Life Science Park Road, Beijing 100084, China.
出版信息
EBioMedicine. 2016 Apr;6:162-170. doi: 10.1016/j.ebiom.2016.02.032. Epub 2016 Feb 20.
BACKGROUND
Type 2 diabetes (T2D) is a risk factor for dysregulation of glomerular filtration rate (GFR) and albuminuria. However, whether the association is causal remains unestablished.
RESEARCH DESIGN AND METHODS
We performed a Mendelian Randomization (MR) analysis in 11,502 participants aged 40 and above, from a well-defined community in Shanghai during 2011-2013, to explore the causal association between T2D and decreased estimated GFR (eGFR) and increased urinary albumin-to-creatinine ratio (uACR). We genotyped 34 established T2D common variants in East Asians, and created a T2D-genetic risk score (GRS). We defined decreased eGFR as eGFR<90ml/min/1.73m(2) and increased uACR as uACR≥30mg/g. We used the T2D_GRS as the instrumental variable (IV) to quantify the causal effect of T2D on decreased eGFR and increased uACR.
RESULTS
Each 1-standard deviation (SD, 3.90 points) increment in T2D_GRS was associated with decreased eGFR: odds ratio (OR)=1.18 (95% confidence interval [CI]: 1.01, 1.30). In the MR analysis, we demonstrated a causal relationship between genetically determined T2D and decreased eGFR (OR=1.47, 95% CI: 1.15, 1.88, P=0.0003). When grouping the genetic loci according to their relations with either insulin secretion (IS) or insulin resistance (IR), we found both IS_GRS and IR_GRS were significantly related to decreased eGFR (both P<0.02). In addition, T2D_GRS and IS_GRS were significantly associated with Log-uACR (both P=0.04).
CONCLUSION
Our results provide novel evidence for a causal association between T2D and decreased eGFR by using MR approach in a Chinese population.
背景
2型糖尿病（T2D）是肾小球滤过率（GFR）失调和蛋白尿的一个风险因素。然而，这种关联是否为因果关系仍未确定。
研究设计与方法
我们对2011年至2013年期间来自上海一个明确界定社区的11502名40岁及以上参与者进行了孟德尔随机化（MR）分析，以探究T2D与估计肾小球滤过率（eGFR）降低及尿白蛋白与肌酐比值（uACR）升高之间的因果关联。我们对东亚人群中34个已确定的T2D常见变异进行了基因分型，并创建了一个T2D遗传风险评分（GRS）。我们将eGFR降低定义为eGFR<90ml/min/1.73m²，将uACR升高定义为uACR≥30mg/g。我们使用T2D_GRS作为工具变量（IV）来量化T2D对eGFR降低和uACR升高的因果效应。
结果
T2D_GRS每增加1个标准差（SD，3.90分）与eGFR降低相关：优势比（OR）=1.18（95%置信区间[CI]：1.01，1.30）。在MR分析中，我们证明了基因决定的T2D与eGFR降低之间存在因果关系（OR=1.47，95%CI：1.15，1.88，P=0.0003）。当根据基因位点与胰岛素分泌（IS）或胰岛素抵抗（IR）的关系对基因位点进行分组时，我们发现IS_GRS和IR_GRS均与eGFR降低显著相关（P均<0.02）。此外，T2D_GRS和IS_GRS与Log-uACR显著相关（P均=0.04）。
结论
我们的结果通过在中国人群中使用MR方法，为T2D与eGFR降低之间的因果关联提供了新的证据。
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