TY - JOUR
T1 - Assessment of the bi-directional relationship between blood mitochondrial DNA copy number and type 2 diabetes mellitus
T2 - a multivariable-adjusted regression and Mendelian randomisation study
AU - Wang, Wenyi
AU - Luo, Jiao
AU - Willems van Dijk, Ko
AU - Hägg, Sara
AU - Grassmann, Felix
AU - `t Hart, Leen M.
AU - van Heemst, Diana
AU - Noordam, Raymond
N1 - Funding Information:
This work was supported by the VELUX Stiftung (grant number 1156) to DvH and RN, and WW and JL were supported with a scholarship from the China Scholarship Council (201907720011 and 201808500155, respectively). SH is supported by the Karolinska Institutet Strategic Research Area in Epidemiology and the Swedish Research Council (2019-01272). FG has received a grant from the Åke Wibergs Foundation (M19-0294).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/10
Y1 - 2022/10
N2 - 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: [Figure not available: see fulltext.]
AB - 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: [Figure not available: see fulltext.]
KW - Mendelian randomisation
KW - Mitochondrial DNA copy number
KW - Prospective analyses
KW - Type 2 diabetes mellitus
UR - http://www.scopus.com/inward/record.url?scp=85134657700&partnerID=8YFLogxK
U2 - 10.1007/s00125-022-05759-6
DO - 10.1007/s00125-022-05759-6
M3 - Article
C2 - 35867128
SN - 0012-186X
VL - 65
SP - 1676
EP - 1686
JO - Diabetologia
JF - Diabetologia
IS - 10
ER -