肥胖与肾功能：两样本孟德尔随机化研究。
Obesity and Kidney Function: A Two-Sample Mendelian Randomization Study.
机构信息
Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
出版信息
Clin Chem. 2022 Mar 4;68(3):461-472. doi: 10.1093/clinchem/hvab249.
BACKGROUND
Obesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD).
METHODS
Using summary data from GIANT (Genetic Investigation of Anthropometric Traits), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), and CKDGen (CKD Genetics), we examined causality and directionality of the association between obesity and kidney function. Bidirectional 2-sample Mendelian randomization (MR) estimated the total causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on kidney function, and vice versa. Effects of adverse obesity and T2D were examined by stratifying BMI variants by their association with WHR and T2D. Multivariable MR estimated the direct causal effects of BMI and WHR on kidney function. The inverse variance weighted random-effects MR for Europeans was the main analysis, accompanied by several sensitivity MR analyses.
RESULTS
One standard deviation (SD ≈ 4.8 kg/m2) genetically higher BMI was associated with decreased estimated glomerular filtration rate (eGFR) [β=-0.032 (95% confidence intervals: -0.036, -0.027) log[eGFR], P = 1 × 10-43], increased blood urea nitrogen (BUN) [β = 0.010 (0.005, 0.015) log[BUN], P = 3 × 10-6], increased urinary albumin-to-creatinine ratio [β = 0.199 (0.067, 0.332) log[urinary albumin-to-creatinine ratio (UACR)], P = 0.003] in individuals with diabetes, and increased risk of microalbuminuria [odds ratios (OR) = 1.15 [1.04-1.28], P = 0.009] and CKD [1.13 (1.07-1.19), P = 3 × 10-6]. Corresponding estimates for WHR and for trans-ethnic populations were overall similar. The associations were driven by adverse obesity, and for microalbuminuria additionally by T2D. While genetically high BMI, unlike WHR, was directly associated with eGFR, BUN, and CKD, the pathway to albuminuria was likely through T2D. Genetically predicted kidney function was not associated with BMI or WHR.
CONCLUSIONS
Genetically high BMI is associated with impaired kidney function, driven by adverse obesity, and for albuminuria additionally by T2D.
背景
肥胖和 2 型糖尿病（T2D）是慢性肾脏病（CKD）的相关危险因素。
方法
利用 GIANT（人体测量特征的遗传研究）、DIAGRAM（糖尿病遗传复制和荟萃分析）和 CKDGen（CKD 遗传学）的汇总数据，我们研究了肥胖与肾功能之间关联的因果关系和方向性。双向 2 样本 Mendelian 随机化（MR）估计了体质指数（BMI）和腰臀比（WHR）对肾功能的总因果效应，反之亦然。通过按与 WHR 和 T2D 的关联对 BMI 变异体进行分层，研究了不良肥胖和 T2D 的影响。多变量 MR 估计了 BMI 和 WHR 对肾功能的直接因果影响。欧洲人的逆方差加权随机效应 MR 是主要分析，同时还进行了几项敏感性 MR 分析。
结果
一个标准差（SD≈4.8kg/m2）的遗传高 BMI 与估算肾小球滤过率（eGFR）降低相关[β=-0.032（95%置信区间：-0.036，-0.027）log[eGFR]，P=1×10-43]，血尿素氮（BUN）升高[β=0.010（0.005，0.015）log[BUN]，P=3×10-6]，糖尿病患者尿白蛋白/肌酐比值升高[β=0.199（0.067，0.332）log[尿白蛋白/肌酐比值（UACR）]，P=0.003]，并且微白蛋白尿风险增加[优势比（OR）=1.15（1.04-1.28），P=0.009]和 CKD[1.13（1.07-1.19），P=3×10-6]。WHR 和跨种族人群的相应估计值总体上相似。这些关联是由不良肥胖引起的，对于微白蛋白尿，还与 T2D 有关。虽然遗传高 BMI 与 eGFR、BUN 和 CKD 直接相关，但与白蛋白尿相关的途径可能是通过 T2D。遗传预测的肾功能与 BMI 或 WHR 无关。
结论
遗传高 BMI 与肾功能受损有关，其原因是不良肥胖，对于白蛋白尿，还与 T2D 有关。
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