Assessment of the bi-directional relationship between blood mitochondrial DNA copy number and type 2 diabetes mellitus: a multivariable-adjusted regression and Mendelian randomisation study,Diabetologia

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Assessment of the bi-directional relationship between blood mitochondrial DNA copy number and type 2 diabetes mellitus: a multivariable-adjusted regression and Mendelian randomisation study
Diabetologia ( IF 8.4 ) Pub Date : 2022-07-22 , DOI: 10.1007/s00125-022-05759-6
Wenyi Wang ₁ , Jiao Luo _{2,

3} , Ko Willems van Dijk _{1,

4,

5} , Sara Hägg ₆ , Felix Grassmann _{6,

7} , Leen M T Hart _{8,

9,

10} , Diana van Heemst ₂ , Raymond Noordam ₂

Affiliation

Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Internal Medicine, Division Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
Leiden Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
Health and Medical University, Potsdam, Germany.
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Biomedical Data Sciences, Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Epidemiology and Data Sciences, Amsterdam University Medical Center, Location VUmc, Amsterdam, the Netherlands.

Aims/hypothesis

Mitochondrial dysfunction, which can be approximated by blood mitochondrial DNA copy number (mtDNA-CN), has been implicated in the pathogenesis of type 2 diabetes mellitus. Thus far, however, insights from prospective cohort studies and Mendelian randomisation (MR) analyses on this relationship are limited. We assessed the association between blood mtDNA-CN and incident type 2 diabetes using multivariable-adjusted regression analyses, and the associations between blood mtDNA-CN and type 2 diabetes and BMI using bi-directional MR.

Methods

Multivariable-adjusted Cox proportional hazard models were used to estimate the association between blood mtDNA-CN and incident type 2 diabetes in 285,967 unrelated European individuals from UK Biobank free of type 2 diabetes at baseline. Additionally, a cross-sectional analysis was performed to investigate the association between blood mtDNA-CN and BMI. We also assessed the potentially causal relationship between blood mtDNA-CN and type 2 diabetes (N=898,130 from DIAGRAM, N=215,654 from FinnGen) and BMI (N=681,275 from GIANT) using bi-directional two-sample MR.

Results

During a median follow-up of 11.87 years, 15,111 participants developed type 2 diabetes. Participants with a higher level of blood mtDNA-CN are at lower risk of developing type 2 diabetes (HR 0.90 [95% CI 0.89, 0.92]). After additional adjustment for BMI and other confounders, these results attenuated moderately and remained present. The multivariable-adjusted cross-sectional analyses showed that higher blood mtDNA-CN was associated with lower BMI (−0.12 [95% CI −0.14, −0.10]) kg/m². In the bi-directional MR analyses, we found no evidence for causal associations between blood mtDNA-CN and type 2 diabetes, and blood mtDNA-CN and BMI in either direction.

Conclusions/interpretation

The results from the present study indicate that the observed association between low blood mtDNA-CN and higher risk of type 2 diabetes is likely not causal.

Graphical abstract

中文翻译：

评估血液线粒体 DNA 拷贝数与 2 型糖尿病之间的双向关系：多变量调整回归和孟德尔随机化研究

目标/假设

线粒体功能障碍，可以通过血液线粒体 DNA 拷贝数 (mtDNA-CN) 来近似，与 2 型糖尿病的发病机制有关。然而，到目前为止，前瞻性队列研究和孟德尔随机化 (MR) 分析对这种关系的见解是有限的。我们使用多变量调整回归分析评估了血液 mtDNA-CN 与事件 2 型糖尿病之间的关联，并使用双向 MR 评估了血液 mtDNA-CN 与 2 型糖尿病和 BMI 之间的关联。

方法

多变量调整 Cox 比例风险模型用于估计来自 UK Biobank 的 285,967 名基线时无 2 型糖尿病的无关欧洲个体的血液 mtDNA-CN 与事件 2 型糖尿病之间的关联。此外，还进行了横断面分析以研究血液 mtDNA-CN 与 BMI 之间的关联。我们还使用双向双样本 MR评估了血液 mtDNA-CN 与 2 型糖尿病（来自 DIAGRAM 的N =898,130，来自 FinnGen 的N =215,654）和 BMI（来自 GIANT 的N =681,275）之间的潜在因果关系。

结果

在 11.87 年的中位随访期间，15,111 名参与者患上了 2 型糖尿病。血液中 mtDNA-CN 水平较高的参与者患 2 型糖尿病的风险较低（HR 0.90 [95% CI 0.89, 0.92]）。在对 BMI 和其他混杂因素进行额外调整后，这些结果适度减弱并保持存在。多变量调整的横断面分析表明，较高的血液 mtDNA-CN 与较低的 BMI 相关（-0.12 [95% CI -0.14, -0.10]）kg/m ²。在双向 MR 分析中，我们没有发现血液 mtDNA-CN 与 2 型糖尿病之间存在因果关系的证据，以及血液 mtDNA-CN 和 BMI 在任一方向上的因果关系。