Department of Epidemiology and Health Statistics, School of Public Health, Hangzhou Medical College, Hangzhou, China.
Department of Orthopaedics, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
J Clin Endocrinol Metab. 2021 Jun 16;106(7):e2547-e2556. doi: 10.1210/clinem/dgab200.
Previous epidemiological evidence showed that type 2 diabetes (T2D) is related with gout. However, the causality and the direction of this association are still not definitely elucidated. We investigated bidirectional associations of T2D and glycemic traits with serum urate concentrations and gout using a Mendelian randomization approach.
Summary statistics from the large-scale genomewide association studies conducted for T2D (Ncase = 62 892, Ncontrol = 596 424), fasting glucose (N = 133 010), fasting insulin (N = 133 010), hemoglobin A1c (N = 123 665), homeostasis model assessment of insulin resistance (N = 46 186), urate (N = 110 347), and gout (Ncase = 2115, Ncontrol = 67 259) among participants of European ancestry were analyzed. For each trait of interest, independent genomewide significant (P < 5 × 10-8) single nucleotide polymorphisms were selected as instrumental variables. The inverse-variance weighted method was used for the primary analyses.
Genetic predisposition to higher risk of T2D [beta = 0.042; 95% confidence interval (CI) = 0.016-0.068; P = 0.002] and higher levels of fasting insulin (beta = 0.756; 95% CI = 0.408-1.102; P = 1.96e-05) were significantly associated with increased serum urate concentrations. Moreover, we found suggestively significant evidence supporting a causal role of fasting insulin on risk of developing gout (odds ratio = 3.06; 95% CI = 0.88-10.61; P = 0.078). In the reverse direction analysis, genetic predisposition to both urate and gout were not associated with T2D or any of 4 glycemic traits being investigated.
This study provides supportive evidence on causal associations of T2D and fasting insulin with serum urate concentrations and a suggestive association of fasting insulin with risk of gout. Future research is required to examine the underlying biological mechanisms on such relationships.
先前的流行病学证据表明，2 型糖尿病（T2D）与痛风有关。然而，这种关联的因果关系和方向仍未得到明确阐明。我们采用孟德尔随机化方法研究了 T2D 和血糖特征与血清尿酸浓度及痛风之间的双向关联。
对欧洲血统参与者进行的 T2D（Ncase=62892，Ncontrol=596424）、空腹血糖（N=133010）、空腹胰岛素（N=133010）、糖化血红蛋白 A1c（N=123665）、胰岛素抵抗的稳态模型评估（N=46186）、尿酸（N=110347）和痛风（Ncase=2115，Ncontrol=67259）的大型全基因组关联研究的汇总统计数据进行了分析。对于每个感兴趣的特征，选择独立的全基因组显著（P<5×10-8）单核苷酸多态性作为工具变量。主要分析采用逆方差加权法。
T2D 风险升高的遗传倾向[β=0.042；95%置信区间（CI）=0.016-0.068；P=0.002]和空腹胰岛素水平升高（β=0.756；95%CI=0.408-1.102；P=1.96e-05）与血清尿酸浓度升高显著相关。此外，我们发现有迹象表明，空腹胰岛素与痛风发病风险之间存在因果关系（比值比=3.06；95%CI=0.88-10.61；P=0.078）。在反向分析中，尿酸和痛风的遗传倾向与 T2D 或正在研究的 4 项血糖特征均无关联。
本研究提供了支持性证据，表明 T2D 和空腹胰岛素与血清尿酸浓度之间存在因果关系，空腹胰岛素与痛风风险之间存在提示性关联。需要进一步的研究来检验这些关系的潜在生物学机制。
