Mitochondrial DNA haplogroups and trajectories of cardiometabolic risk factors during childhood and adolescence: a prospective cohort study

Background Mitochondria are organelles responsible for converting glucose into energy. Mitochondrial DNA is exclusively maternally inherited by offspring. The role of mitochondrial DNA haplogroups in the aetiology of cardiometabolic disease risk is not well understood. Methods We examined the sex-specific association between European mitochondrial DNA haplogroups and trajectories of nine cardiometabolic risk factors from birth to 18 years in a prospective English birth cohort. Mitochondrial haplogroups were analysed according to common European haplogroups; H,U,J,T,K,V,W,I and X. Nine cardiometabolic risk factors measured over varying times from birth/mid-childhood to age 18 years included body mass index (BMI), fat mass and lean mass, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, high-density lipoprotein cholesterol (HDL-c), non HDL-c and triglycerides. Fractional polynomial and linear spline multilevel models stratified by sex explored the sex-specific association between haplogroups and risk factor trajectories. Results Among 6,360-7,954 participants with 22,864-79,178 repeated measures per outcome, we found no strong evidence that haplogroups U,T,J,K and W were associated with trajectories of cardiometabolic risk factors across childhood and adolescence compared to haplogroup H. In females, haplogroup V was associated with 4.0% (95% CI: 1.4, 6.7) lower BMI at age 7 years and 9.3% (95% CI: 1.9, 16.7) lower fat mass at age 9, though differences did not persist at age 18. Haplogroup X was associated with 1.3kg (95% CI: 0.5, 2.2) lower lean mass and 16.4% (95% CI: 3.5, 29.3) lower fat mass at age 9; associations with lower lean mass persisted at 18 years whereas associations with fat mass did not. In males, haplogroup I was associated with 2.4% (95% CI: 0.2, 4.6) higher BMI at age 7; this difference widened to 5.1% (95% CI: 0.9,9.3) at 18 years. Conclusion Our study demonstrated some evidence of sex-specific associations between mitochondrial DNA haplogroups V, I and X and trajectories of adiposity during childhood and adolescence. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (). This research was specifically funded by the UK Medical Research Council (grant ref: MR/K002767/1). KON is supported by a HRB Emerging Investigator Award (EIA-FA-2019-007 SCaRLeT). LDH is supported by Career Development Awards from the UK Medical Research Council (grants MR/M020894/1 and MR/M009351/1, respectively). LMOK is supported by a Health Research Board (HRB) of Ireland Emerging Investigator Award (EIA-FA-2019-007 SCaRLeT) and a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1). AF, LDH, ES and SR work in a unit that receives funds from the UK Medical Research Council (grant MC\_UU\_00011/1, MC\_UU\_00011/3, MC\_UU\_00011/6). These funding sources had no role in the design and conduct of this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data are available upon submission and approval of a research proposal to the ALSPAC Executive. Further information can be found at