Abruptio placentae risk and genetic variations in mitochondrial biogenesis and oxidative phosphorylation: replication of a candidate gene association study.
Abruptio placentae risk and genetic variations in mitochondrial biogenesis and oxidative phosphorylation: replication of a candidate gene association study.
复制标题
线粒体生物发生和氧化磷酸化中的胎盘胎盘风险和遗传变异：候选基因关联研究的复制。
DOI：
10.1016/j.ajog.2018.08.042
复制
发表时间：
2018-12
影响因子：
9.8
通讯作者：
Williams MA
中科院分区：
文献类型：
--
作者：
Workalemahu T;Enquobahrie DA;Gelaye B;Thornton TA;Tekola-Ayele F;Sanchez SE;Garcia PJ;Palomino HG;Hajat A;Romero R;Ananth CV;Williams MA
胎盘早剥是一种复杂的多因素疾病，与孕产妇和新生儿的死亡和发病率有关。胎盘早剥的高复发率，在胎盘早剥妇女中遗传性血栓形成的高流行率，以及患有这种疾病的妇女家庭中病例的聚集，支持了遗传易感性的可能性。以前的全基因组和候选基因关联研究已经发现线粒体生物发生和氧化磷酸化基因中的单核苷酸多态可能与胎盘早剥风险相关。线粒体生物发生和氧化磷酸化的紊乱导致线粒体功能障碍，可导致滋养层细胞分化和侵袭的损害，以及包括胎盘早剥在内的几种产科并发症。这项研究的目的是确定一项候选遗传关联研究的结果是否可以复制，该研究表明DNA变异(与线粒体生物发生和氧化磷酸化有关)与胎盘早剥之间存在联系。这项研究是在胎盘早剥遗传流行病学研究的参与者(507例胎盘早剥病例和1090名对照受试者)中进行的。使用9个线粒体生物发生和氧化磷酸化基因(CAMK2B、NR1H3、PPARG、PRKCA、THRB、COX5A、NDUFA10、NDUFA12和NDUFC2)中11个单核苷酸多态的胎盘风险增加等位基因计算加权遗传风险分数，这是一项先前在秘鲁胎盘早剥流行病学研究中报道的研究，该研究的设计和研究人群与胎盘早剥遗传流行病学研究类似。Logistic回归模型适合于检验加权遗传风险评分(第1、2四分位、25-50百分位数、3、50-70百分位数和4分位数、75百分位数)与胎盘早剥风险的关系，并对人群混合(前4个主成分)、母亲年龄、婴儿性别和先兆子痫进行调整。加权遗传风险分数也被建模为连续预测因子。为了评估修改的潜在效果，重复分析了由先兆子痫状态、母亲年龄(≥35岁对18-34岁)和婴儿性别定义的不同阶层。胎盘早剥患者更有可能患有先兆子痫，胎龄较短，婴儿出生体重较低。四分位2(得分，12.6-13.8)、四分位3(得分，13.9-15.0)和四分位(得分，≥15.1)参与者的遗传风险分数分别为1.45倍(95%可信区间，1.04-2.02；P=0.03)、1.42倍(95%可信区间，1.02-1.98；P=0.04)和1.75倍(95%可信区间，1.27-2.42；P=7.0E-04)与四分位数1相比，胎盘早剥的几率分别更高(得分12.6；趋势=.0003)。评分每增加1个单位，胎盘早剥的风险增加1.12倍(95%可信区间为1.05~1.19；P=3.0×1004)。在子痫前期患者中，第四分位数的女性胎盘早剥的几率是第一分位数的3.92倍(95%可信区间为1.48-10.36；P=0.01)。在血压正常的女性中，第四分位数的女性胎盘早剥的几率是第一分位数的1.57倍(95%可信区间为1.11-2.21；P=0.01)。我们没有观察到由母亲年龄或婴儿性别定义的不同阶层之间的关联差异。在这项研究中，我们复制了之前的发现，并为编码参与线粒体生物发生和氧化磷酸化途径的基因的DNA变体提供了强有力的证据，这可能导致胎盘早剥。这些结果揭示了DNA变异的机制，这些DNA变异编码线粒体功能中的蛋白质，从而导致胎盘早剥的风险。通过改进对母体线粒体生物发生/氧化磷酸化途径的生物学理解，以及确定哪些妇女可能是胎盘早剥的高危人群，可以加强降低胎盘早剥风险的治疗努力。
Abruptio placentae is a complex multifactorial disease that is associated with maternal and neonatal death and morbidity. Abruptio placentae’s high recurrence rate, high prevalence of heritable thrombophilia among women with abruptio placentae, and aggregation of cases in families of women with the disease support the possibility of a genetic predisposition. Previous genome-wide and candidate gene association studies have identified single nucleotide polymorphisms in mitochondrial biogenesis and oxidative phosphorylation genes that potentially are associated with abruptio placentae risk. Perturbations in mitochondrial biogenesis and oxidative phosphorylation, which results in mitochondrial dysfunction, can lead to the impairment of differentiation and invasion of the trophoblast and to several obstetrics complications that include abruptio placentae. The purpose of this study was to determine whether the results of a candidate genetic association study that indicated a link between DNA variants (implicated in mitochondrial biogenesis and oxidative phosphorylation) and abruptio placentae could be replicated. The study was conducted among participants (507 abruptio placentae cases and 1090 control subjects) of the Placental Abruption Genetic Epidemiology study. Weighted genetic risk scores were calculated with the use of abruptio placentae risk-increasing alleles of 11 single nucleotide polymorphisms in 9 mitochondrial biogenesis and oxidative phosphorylation genes (CAMK2B, NR1H3, PPARG, PRKCA, THRB, COX5A, NDUFA10, NDUFA12, and NDUFC2), which previously was reported in the Peruvian Abruptio Placentae Epidemiology study, a study with similar design and study population to the Placental Abruption Genetic Epidemiology study. Logistic regression models were fit to examine associations of weighted genetic risk scores (quartile 1, <25th percentile; quartile 2, 25–50th percentile; quartile 3, 50–70th percentile, and quartile 4, >75th percentile) with risk of abruptio placentae, adjusted for population admixture (the first 4 principal components), maternal age, infant sex, and preeclampsia. The weighted genetic risk score was also modeled as a continuous predictor. To assess potential effect modification, analyses were repeated among strata that were defined by preeclampsia status, maternal age (≥35 vs 18–34 years), and infant sex. Abruptio placentae cases were more likely to have preeclampsia, shorter gestational age, and lower infant birthweight. Participants in quartile 2 (score, 12.6–13.8), quartile 3 (score, 13.9–15.0) and quartile 4 (score, ≥15.1) had a genetic risk score of 1.45-fold (95% confidence interval, 1.04–2.02; P=.03), a 1.42-fold (95% confidence interval, 1.02–1.98; P=.04), and a 1.75-fold (95% confidence interval, 1.27–2.42; P=7.0E-04) higher odds of abruptio placentae, respectively, compared with those in quartile 1 (score,<12.6; P-for trend=.0003). The risk of abruptio placentae was 1.12-fold (95% confidence interval, 1.05–1.19; P=3.0×1004) higher per 1-unit increase in the score. Among women with preeclampsia, those in quartile 4 had a 3.92-fold (95% confidence interval, 1.48–10.36; P=.01) higher odds of abruptio placentae compared with women in quartile 1. Among normotensive women, women in quartile 4 had a 1.57-fold (95% confidence interval, 1.11–2.21; P=.01) higher odds of abruptio placentae compared with those in quartile 1 (P-for interaction=.12). We did not observe differences in associations among strata defined by maternal age or infant sex. In this study, we replicated previous findings and provide strong evidence for DNA variants that encode for genes that are involved in mitochondrial biogenesis and oxidative phosphorylation pathways, which confers risk for abruptio placentae. These results shed light on the mechanisms that implicate DNA variants that encode for proteins in mitochondrial function that are responsible for abruptio placentae risk. Therapeutic efforts to reduce risk of abruptio placentae can be enhanced by improved biologic understanding of maternal mitochondrial biogenesis/oxidative phosphorylation pathways and identification of women who would be at high risk for abruptio placentae.
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影响因子：
7.7
作者：
Aschard H;Tobin MD;Hancock DB;Skurnik D;Sood A;James A;Vernon Smith A;Manichaikul AW;Campbell A;Prins BP;Hayward C;Loth DW;Porteous DJ;Strachan DP;Zeggini E;O'Connor GT;Brusselle GG;Boezen HM;Schulz H;Deary IJ;Hall IP;Rudan I;Kaprio J;Wilson JF;Wilk JB;Huffman JE;Hua Zhao J;de Jong K;Lyytikäinen LP;Wain LV;Jarvelin MR;Kähönen M;Fornage M;Polasek O;Cassano PA;Barr RG;Rawal R;Harris SE;Gharib SA;Enroth S;Heckbert SR;Lehtimäki T;Gyllensten U;Understanding Society Scientific Group;Jackson VE;Gudnason V;Tang W;Dupuis J;Soler Artigas M;Joshi AD;London SJ;Kraft P
通讯作者：
Kraft P
影响因子：
5.4
作者：
Aschard, Hugues;Zaitlen, Noah;Kraft, Peter
通讯作者：
Kraft, Peter
影响因子：
3.8
作者：
Ananth, Cande V.;Elsasser, Denise A.;Rozen, Rima R.
通讯作者：
Rozen, Rima R.
影响因子：
5.3
作者：
Ananth, Cande V.;Peltier, Morgan R.;Rozen, Rima R.
通讯作者：
Rozen, Rima R.
叶酸缺乏会损害小鼠的蜕膜化并改变基因组的甲基化模式
影响因子：
4
作者：
Geng, Yanqing;Gao, Rufei;He, Junlin
通讯作者：
He, Junlin