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Placental genome and maternal-placental genetic interactions: A genome-wide and candidate gene association study of placental abruption

机译：胎盘基因组与母胎盘遗传相互作用：胎盘早剥的全基因组和候选基因关联研究

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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. (Résumé d'auteur)
机译：尽管现有证据支持遗传学在胎盘早剥（PA）发病机理中的作用，但尚未研究PA相关的胎盘基因组变异和母体-胎盘遗传相互作用。使用Illumina的Cardio-Metabochip平台对从秘鲁胎盘早剥病流行病学研究参与者中收集的孕妇血液和胎盘样本进行基因分型。我们检查了来自280个PA病例和244个对照的线粒体生物发生和胎盘DNA中的氧化磷酸化途径的32个候选基因中的118,782个全基因组SNP和333个SNP。我们评估了候选基因SNPS和两个印迹区域（IGF2 / H19和C19MC）中的母体-胎盘相互作用。单变量和惩罚逻辑回归模型适合估计比值比。我们使用加权遗传风险评分（WGRS）和重复的十倍交叉验证，检验了多个SNP对PA风险的综合影响。多项式模型用于研究母体-胎盘遗传相互作用。在胎盘全基因组和候选基因分析中，错误发现率校正后无SNP显着。最高的全基因组关联研究（GWAS）命中是rs544201，rs1484464（CTNNA2），rs4149570（TNFRSF1A）和rs13055470（ZNRF3）（p值：1.11e-05至3.54e-05）。 GWAS的前200个SNP代表了参与细胞周期，生长和增殖的基因。候选基因命中率最高的是rs16949118（COX10）和rs7609948（THRB）（p值：6.00e-03和8.19e-03）。使用来自GWAS的SNP进行交叉验证并进行候选基因分析，基于交叉验证的WGRS最高四分位数的参与者具有8.40倍（95％CI：5.8-12.56）和4.46倍（95％CI：2.94-6.72）与最低四分位数的参与者相比，PA的几率更高。我们发现母体-胎盘遗传相互作用对PPARG中两个SNPs的PA风险（chr3：12313450和chr3：12412978）以及母体对C19MC和IGF2 / H19区域中多个SNP的印迹作用。胎盘基因组的变异以及母体-胎盘遗传变异之间的相互作用可能会导致PA风险。较大的研究可能有助于增进我们对PA发病机制的了解。 （Résuméd'auteur）

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