| Title: | 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 |
| Journal: | Diabetologia |
| Published: | 22 Jul 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35867128/ |
| DOI: | https://doi.org/10.1007/s00125-022-05759-6 |
| URL: | https://link.springer.com/content/pdf/10.1007/s00125-022-05759-6.pdf |
Publication 10371
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Abstract
Aims/hypothesisMitochondrial 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.MethodsMultivariable-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.ResultsDuring 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/interpretationThe 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</p>
8 Authors
- Wenyi Wang
- Jiao Luo
- Ko Willems van Dijk
- Sara Hägg
- Felix Grassmann
- Leen M. `t Hart
- Diana van Heemst
- Raymond Noordam
1 Application
| Application ID | Title |
|---|---|
| 22474 | Genetic determinants for insulin-dependent type 2 diabetes mellitus |
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