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Detailed Analysis of Variation at and around Mitochondrial Position 16189 in a Large Finnish Cohort Reveals No Significant Associations with Early Growth or Metabolic Phenotypes at Age 31 Years

Women’s Centre Level 3 (S.D., J.P.), Nuffield Department of Obstetrics and Gynecology, John Radcliffe Hospital, Oxford Centre for Diabetes, Endocrinology, and Metabolism (S.D., A.J.B., M.I.M.), and Wellcome Trust Centre for Human Genetics (M.I.M.), University of Oxford, Oxford OX3 7LJ, United Kingdom; Department of Epidemiology and Public Health (U.S., P.E., M.-R.J.), and Institute of Reproductive and Developmental Biology (S.F.), Imperial College London, London SW7 2AZ, United Kingdom; and Departments of Clinical Chemistry (A.R.), Obstetrics and Gynecology (H.M., A.P., A.-L.H.), and Public Health Science and General Practice (M.-R.H.), University of Oulu, and National Public Health Institute (A.P.), 90220 Oulu, Finland

Address all correspondence and requests for reprints to: Professor Mark I. McCarthy, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LJ, United Kingdom. E-mail: mark.mccarthy{at}drl.ox.ac.uk; or Professor Joanna Poulton, Nuffield Department of Obstetrics and Gynecology, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, United Kingdom. E-mail: joanna.poulton{at}obs-gyn.ox.ac.uk.

Context: Mitochondrial dysfunction is increasingly implicated in pathogenesis of adult metabolic disease. Rare mitochondrial (mt) DNA mutations impair glucose homeostasis, but the contribution of common variants is unclear. In small studies, variation within the OriB origin of replication (at mt16189 in particular) has been associated with both early growth and adult metabolic phenotypes and may contribute to life-course relationships between the two.

Objective: The aim was to study a large well-characterized cohort to determine whether previously reported small-scale associations between OriB sequence variation and early growth and adult metabolic phenotypes are robust.

Design/Setting/Participants: This was a genetic association study of 5470 individuals from the population-based Northern Finland Birth Cohort of 1966, followed prospectively from pregnancy to age 31 yr.

Main Outcome Measures: We measured indices of early growth (including birth weight, placental weight, and ponderal index) and adult metabolic homeostasis (including body mass index, fasting glucose and insulin, indices of insulin action and secretion) and their relationship to variation in the OriB region.

Results: Previously reported associations could not be confirmed. There were no significant (P < 0.01, uncorrected) associations between OriB sequence variation and measures of early growth including birth weight (P = 0.52, comparing individuals with mt16189T to those with a homopolymeric C-tract) and placental weight (P = 0.49). There were no significant associations with adult metabolic phenotypes including fasting glucose (P = 0.07), fasting insulin (P = 0.42), and homeostatic model assessment-derived measures of insulin sensitivity or secretion (P = 0.45 and P = 0.56, respectively).

Conclusion: Despite substantial power to detect previously reported effects, mtDNA variations around OriB are not major contributors to variation in early growth and metabolic phenotypes during early adulthood.