Denis Marie, Enquobahrie Daniel A, Tadesse Mahlet G, Gelaye Bizu, Sanchez Sixto E, Salazar Manuel, Ananth Cande V, Williams Michelle A
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America; UMR AGAP (Amélioration Génétique et Adaptation des Plantes méditerranéennes et tropicales), CIRAD, Montpellier, France.
Center for Perinatal Studies, Swedish Medical Center, Seattle, Washington, United States of America; Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2014 Dec 30;9(12):e116346. doi: 10.1371/journal.pone.0116346. eCollection 2014.
While available evidence supports the role of genetics in the pathogenesis of placental abruption (PA), PA-related placental genome variations and maternal-placental genetic interactions have not been investigated. Maternal blood and placental samples collected from participants in the Peruvian Abruptio Placentae Epidemiology study were genotyped using Illumina's Cardio-Metabochip platform. We examined 118,782 genome-wide SNPs and 333 SNPs in 32 candidate genes from mitochondrial biogenesis and oxidative phosphorylation pathways in placental DNA from 280 PA cases and 244 controls. We assessed maternal-placental interactions in the candidate gene SNPS and two imprinted regions (IGF2/H19 and C19MC). Univariate and penalized logistic regression models were fit to estimate odds ratios. We examined the combined effect of multiple SNPs on PA risk using weighted genetic risk scores (WGRS) with repeated ten-fold cross-validations. A multinomial model was used to investigate maternal-placental genetic interactions. In placental genome-wide and candidate gene analyses, no SNP was significant after false discovery rate correction. The top genome-wide association study (GWAS) hits were rs544201, rs1484464 (CTNNA2), rs4149570 (TNFRSF1A) and rs13055470 (ZNRF3) (p-values: 1.11e-05 to 3.54e-05). The top 200 SNPs of the GWAS overrepresented genes involved in cell cycle, growth and proliferation. The top candidate gene hits were rs16949118 (COX10) and rs7609948 (THRB) (p-values: 6.00e-03 and 8.19e-03). Participants in the highest quartile of WGRS based on cross-validations using SNPs selected from the GWAS and candidate gene analyses had a 8.40-fold (95% CI: 5.8-12.56) and a 4.46-fold (95% CI: 2.94-6.72) higher odds of PA compared to participants in the lowest quartile. We found maternal-placental genetic interactions on PA risk for two SNPs in PPARG (chr3:12313450 and chr3:12412978) and maternal imprinting effects for multiple SNPs in the C19MC and IGF2/H19 regions. Variations in the placental genome and interactions between maternal-placental genetic variations may contribute to PA risk. Larger studies may help advance our understanding of PA pathogenesis.
虽然现有证据支持遗传学在胎盘早剥（PA）发病机制中的作用，但与PA相关的胎盘基因组变异以及母胎遗传相互作用尚未得到研究。使用Illumina公司的心脏代谢芯片平台对从秘鲁胎盘早剥流行病学研究参与者中收集的母血和胎盘样本进行基因分型。我们在来自280例PA病例和244例对照的胎盘DNA中，检测了118,782个全基因组单核苷酸多态性（SNP）以及线粒体生物发生和氧化磷酸化途径中32个候选基因的333个SNP。我们评估了候选基因SNP以及两个印记区域（IGF2/H19和C19MC）中的母胎相互作用。采用单变量和惩罚逻辑回归模型来估计比值比。我们使用加权遗传风险评分（WGRS）并进行重复十折交叉验证，研究了多个SNP对PA风险的综合影响。采用多项式模型来研究母胎遗传相互作用。在胎盘全基因组和候选基因分析中，经过错误发现率校正后，没有SNP具有显著性。全基因组关联研究（GWAS）中最显著的位点是rs544201、rs1484464（CTNNA2）、rs4149570（TNFRSF1A）和rs13055470（ZNRF3）（p值：1.11e - 05至3.54e - 05）。GWAS中排名前200的SNP所富集的基因涉及细胞周期、生长和增殖。候选基因中最显著的位点是rs16949118（COX10）和rs7609948（THRB）（p值：6.00e - 03和8.19e - 03）。基于使用从GWAS和候选基因分析中选择的SNP进行交叉验证，处于WGRS最高四分位数的参与者患PA的几率比处于最低四分位数的参与者高8.40倍（95%置信区间：5.8 - 12.56）和4.46倍（95%置信区间：2.94 - 6.72）。我们发现PPARG基因中两个SNP（chr3:12313450和chr3:12412978）存在母胎遗传相互作用影响PA风险，以及C19MC和IGF2/H19区域中多个SNP存在母体印记效应。胎盘基因组变异以及母胎遗传变异之间的相互作用可能导致PA风险。更大规模的研究可能有助于增进我们对PA发病机制的理解。
