Type 2 Diabetes, Diabetes Genetic Score and Risk of Decreased Renal Function and Albuminuria: A Mendelian Randomization Study.
Type 2 Diabetes, Diabetes Genetic Score and Risk of Decreased Renal Function and Albuminuria: A Mendelian Randomization Study.
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2 型糖尿病、糖尿病遗传评分以及肾功能下降和蛋白尿的风险：孟德尔随机研究。
DOI：
10.1016/j.ebiom.2016.02.032
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发表时间：
2016-04
期刊：
影响因子：
11.1
通讯作者：
Ning G
中科院分区：
文献类型：
--
作者：
Xu M;Bi Y;Huang Y;Xie L;Hao M;Zhao Z;Xu Y;Lu J;Chen Y;Sun Y;Qi L;Wang W;Ning G
2型糖尿病（T2 D）是肾小球滤过率（GFR）和白蛋白尿失调的危险因素。然而，这种关联是否具有因果关系尚未确定。我们对2011-2013年期间来自上海一个明确定义的社区的11，502名40岁及以上的参与者进行了孟德尔随机化（MR）分析，以探索T2 D与估计GFR（eGFR）降低和尿白蛋白/肌酐比值（uACR）升高之间的因果关系。我们对东亚人中34种T2 D常见变异进行了基因分型，并创建了T2 D遗传风险评分（GRS）。我们将eGFR降低定义为eGFR < 90 ml/min/1.73 m2，将uACR升高定义为uACR ≥ 30 mg/g。我们使用T2D_GRS作为工具变量（IV）来量化T2 D对eGFR降低和uACR升高的因果效应。T2D_GRS每增加1个标准差（SD，3.90分）与eGFR降低相关：比值比（OR）= 1.18（95%置信区间[CI]：1.01，1.30）。在MR分析中，我们证明了遗传决定的T2 D和eGFR降低之间的因果关系（OR = 1.47，95% CI：1.15，1.88，P = 0.0003）。根据与胰岛素分泌（IS）或胰岛素抵抗（IR）的关系对基因座进行分组，发现IS_GRS和IR_GRS均与eGFR降低显著相关（均P < 0.02）。此外，T2 D_GRS和IS_GRS与Log-uACR显着相关（均P = 0.04）。我们的研究结果提供了新的证据，通过在中国人群中使用MR方法，证明T2 D和eGFR降低之间存在因果关系。进行了一项MR研究，以探索T2 D与肾功能下降之间的因果关系。加权T2 D遗传风险评分（GRS）用作工具变量（IV）。T2D_GRS越高，肾小球滤过率（GFR）降低的风险越高。通过IV估计的T2 D可能与MR分析中的肾功能降低风险存在因果关系。流行病学和临床研究表明，2型糖尿病（T2 D）是肾功能失调和蛋白尿的危险因素，强化糖尿病治疗与更好的肾脏结局相关，提示T2 D与肾脏结局之间可能存在因果关系。近年来，以遗传变异为工具变量的孟德尔随机化（MR）方法已被广泛应用于群体研究中的因果关系评估，因为遗传等位基因在配子形成过程中随机分配，并独立于潜在的混杂因素遗传，并表示为终身暴露，这可以对抗混杂或反向因果关系或短期干预等偏倚。我们发现，在11，502名社区居住的中国成年人中，代表T2 D易感性的遗传风险评分而不是其他代谢特征与肾功能下降显著相关，依赖于肥胖，血脂和高血压。这些发现首次提供了新的证据，证明遗传决定的T2 D与使用MR的肾功能下降之间存在因果关系。
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. 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 < 90 ml/min/1.73 m2 and increased uACR as uACR ≥ 30 mg/g. We used the T2D_GRS as the instrumental variable (IV) to quantify the causal effect of T2D on decreased eGFR and increased uACR. 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). Our results provide novel evidence for a causal association between T2D and decreased eGFR by using MR approach in a Chinese population. A MR study was conducted to explore the causal association between T2D and decreased renal function. Weighted T2D genetic risk score (GRS) was used as the instrumental variable (IV). A higher T2D_GRS was associated with higher risk of decreased glomerular filtration rate (GFR). T2D estimated by the IV may causally associate with risk of decreased renal function in the MR analysis. Epidemiological and clinical studies show that type 2 diabetes (T2D) is a risk factor for dysregulation of kidney function and albuminuria, intensive diabetes treatment was associated with better renal outcomes, suggesting a possible causal link between T2D and renal outcomes. Recently, the Mendelian Randomization (MR) approach using genetic variants as the instrumental variable has been widely used for assessing causality in population studies, because the genetic alleles are allocated randomly during gamete formation and are inherited independent of potential confounding factors and represented as a life-long exposure, which could oppose the bias such as confounding or reverse causation, or short-term intervention. We found that in 11,502 community dwelling Chinese adults, a genetic risk score representing the susceptibility to T2D but not other metabolic traits was significantly associated with decreased renal function, in dependent of obesity, lipids and high blood pressure. These findings for the first time provided novel evidence for a causal relationship between genetically determined T2D and decreased kidney function by using MR.