Das Sreena, Bennett Amanda J, Sovio Ulla, Ruokonen Aimo, Martikainen Hannu, Pouta Anneli, Hartikainen Anna-Liisa, Franks Stephen, Elliott Paul, Poulton Joanna, Järvelin Marjo-Riitta, McCarthy Mark I
Women's Centre Level 3, University of Oxford, Oxford OX3 7LJ, United Kingdom.
J Clin Endocrinol Metab. 2007 Aug;92(8):3219-23. doi: 10.1210/jc.2007-0702. Epub 2007 May 29.
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.
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.
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.
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).
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.
线粒体功能障碍在成人代谢性疾病的发病机制中所起的作用日益受到关注。罕见的线粒体（mt）DNA突变会损害葡萄糖稳态，但常见变异的作用尚不清楚。在一些小型研究中，复制起点OriB内的变异（尤其是mt16189处）与早期生长及成人代谢表型均有关联，可能在两者的生命历程关系中发挥作用。
本研究旨在对一个特征明确的大型队列进行研究，以确定先前报道的OriB序列变异与早期生长及成人代谢表型之间的小规模关联是否可靠。
设计/地点/参与者：这是一项对来自1966年基于人群的芬兰北部出生队列的5470名个体进行的基因关联研究，从孕期开始进行前瞻性随访直至31岁。
我们测量了早期生长指标（包括出生体重、胎盘重量和 ponderal指数）以及成人代谢稳态指标（包括体重指数、空腹血糖和胰岛素、胰岛素作用和分泌指标），并研究了它们与OriB区域变异的关系。
先前报道的关联未能得到证实。OriB序列变异与早期生长指标之间无显著（P<0.01，未校正）关联，包括出生体重（将mt16189T个体与具有同聚物C序列的个体进行比较，P = 0.52）和胎盘重量（P = 0.49）。与成人代谢表型也无显著关联，包括空腹血糖（P = 0.07）、空腹胰岛素（P = 0.42）以及基于稳态模型评估得出的胰岛素敏感性或分泌指标（分别为P = 0.45和P = 0.56）。
尽管有足够的能力检测先前报道的效应，但OriB周围的mtDNA变异并非成年早期早期生长和代谢表型变异的主要影响因素
