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.
Diabetologia. 2022 Oct;65(10):1676-1686. doi: 10.1007/s00125-022-05759-6. Epub 2022 Jul 22.
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.
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.
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/m. 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.
目的/假设：线粒体功能障碍可以通过血液线粒体 DNA 拷贝数（mtDNA-CN）来近似评估，它与 2 型糖尿病的发病机制有关。然而，迄今为止，关于这种关系的前瞻性队列研究和孟德尔随机化（MR）分析的结果有限。我们使用多变量调整回归分析评估了血液 mtDNA-CN 与 2 型糖尿病发病之间的关联，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。
我们使用多变量调整的 Cox 比例风险模型来估计英国生物银行 285967 名无 2 型糖尿病基线个体的血液 mtDNA-CN 与 2 型糖尿病发病之间的关联。此外，还进行了一项横断面分析，以研究血液 mtDNA-CN 与 BMI 之间的关联。我们还使用双向两样本 MR 评估了血液 mtDNA-CN 与 2 型糖尿病（来自 DIAGRAM 的 N=898130 名，来自 FinnGen 的 N=215654 名）和 BMI（来自 GIANT 的 N=681275 名）之间的潜在因果关系。
在中位数为 11.87 年的随访期间，有 15111 名参与者发生了 2 型糖尿病。血液 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]）。在进一步调整 BMI 和其他混杂因素后，这些结果适度减弱，但仍然存在。多变量调整的横断面分析显示，较高的血液 mtDNA-CN 与较低的 BMI 相关（-0.12 [95%CI -0.14,-0.10]）kg/m。在双向 MR 分析中，我们没有发现血液 mtDNA-CN 与 2 型糖尿病之间以及血液 mtDNA-CN 与 BMI 之间的因果关系的证据。
结论/解释：本研究的结果表明，观察到的低血液 mtDNA-CN 与 2 型糖尿病风险增加之间的关联可能不是因果关系。
