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

Wang, W.Y.; Luo, J.; Dijk, K.W. van; Hagg, S.; Grassmann, F.; Hart, L.M. 't; ... ; Noordam, R. (2022)

Article / Letter to editor

Aims/hypothesis: Mitochondrial dysfunction, which can be approximated by blood mitochondrial DNA copy number (mtDNACN), 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 DIAG RAM, 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 crosssectional analyses showed that higher blood mtDNA-CN was associated with lower BMI (-0.12 [95% CI -0.14, -0.10]) kg/m(2). 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 mtDNACI\ and higher risk of type 2 diabetes is likely not causal.

• Mendelian randomisation
• Mitochondrial DNA copy number
• Prospective analyses
• Type 2 diabetes mellitus

• All authors: Wang, W.Y.; Luo, J.; Dijk, K.W. van; Hagg, S.; Grassmann, F.; Hart, L.M. 't; Heemst, D. van; Noordam, R.
• Date: 2022-07-22
• Journal: Diabetologia
• Volume: 65
• Pages: 1676 - 1686
• DOI: doi:10.1007/s00125-022-05759-6