城市多民族队列中母体终身压力与胎盘线粒体 DNA 突变的相关性。
Associations Between Maternal Lifetime Stress and Placental Mitochondrial DNA Mutations in an Urban Multiethnic Cohort.
机构信息
Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
出版信息
Biol Psychiatry. 2021 Mar 15;89(6):570-578. doi: 10.1016/j.biopsych.2020.09.013. Epub 2020 Sep 18.
BACKGROUND
Disrupted placental functioning due to stress can have lifelong implications. Cumulative stress and trauma are likely to have lasting impacts on maternal physiological functioning and offspring development, resulting in increased risk for later-life complex disorders for which racial disparities exist.
METHODS
This study examined the association between maternal lifetime stress and placental mitochondrial DNA mutational load in an urban multiethnic cohort. Maternal lifetime exposure to stressful events was assessed using the validated Life Stressor Checklist-Revised. Whole mitochondrial DNA sequencing was performed and mutations were determined for 365 placenta samples with complete exposure and covariate data. Multivariable regression was used to model maternal lifetime stress in relation to placental mitochondrial DNA mutational load. Racial/ethnic differences were examined by cross-product terms and contrast statements. Gene-wise analyses were conducted.
RESULTS
We identified 13,189 heteroplasmies (Phred score > 10,000, minor allele frequency < 0.5, number of mutant reads > 1). Women experiencing increased psychosocial stress over their lifetime exhibited a higher number of total placental mitochondrial mutations (β = .23, 95% confidence interval = .03 to .42) and heteroplasmic mutations (β = .18, 95% confidence interval = .05 to .31) but not homoplasmic mutations (β = -.008, 95% confidence interval = -.03 to .01); the strongest associations were observed among Black women and genes coding for NADH dehydrogenase and cytochrome c oxidase subunits.
CONCLUSIONS
Cumulative maternal lifetime stress is associated with a greater mitochondrial mutational load, particularly among Black women. The impact of racial/ethnic differences in mutational load on placental function directly affecting offspring development and/or leading to chronic disease disparities warrants further investigation.
背景
由于压力导致的胎盘功能紊乱可能会产生终身影响。累积的压力和创伤很可能对产妇的生理功能和后代的发育产生持久影响，从而增加了晚年出现复杂疾病的风险，而这些疾病存在种族差异。
方法
本研究在一个城市的多民族队列中，检查了产妇终生压力与胎盘线粒体 DNA 突变负荷之间的关联。使用经过验证的生活应激检查表修订版评估产妇一生中暴露于应激事件的情况。对具有完整暴露和协变量数据的 365 个胎盘样本进行全线粒体 DNA 测序，并确定突变。多变量回归用于模拟产妇一生中的压力与胎盘线粒体 DNA 突变负荷之间的关系。通过交叉乘积项和对比语句检查种族/民族差异。进行了基因分析。
结果
我们鉴定出了 13189 个异质体（Phred 评分>10000，次要等位基因频率<0.5，突变读取数>1）。在一生中经历更多心理社会压力的女性表现出更高数量的总胎盘线粒体突变（β=0.23，95%置信区间 0.03 至 0.42）和异质体突变（β=0.18，95%置信区间 0.05 至 0.31），但同质体突变（β=-0.008，95%置信区间-0.03 至 0.01）则没有；在黑人女性和编码 NADH 脱氢酶和细胞色素 c 氧化酶亚基的基因中观察到最强的关联。
结论
累积的产妇一生中的压力与更大的线粒体突变负荷相关，尤其是在黑人女性中。突变负荷的种族/民族差异对胎盘功能的直接影响，进而影响后代的发育和/或导致慢性疾病的差异，值得进一步研究。
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