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Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia.

ABSTRACT: In utero interactions between incompatible maternal and fetal genotypes are a potential mechanism for the onset or progression of pregnancy related diseases such as pre-eclampsia (PE). However, the optimal analytical approach and study design for evaluating incompatible maternal/offspring genotype combinations is unclear.Using simulation, we estimated the type I error and power of incompatible maternal/offspring genotype models for two analytical approaches: logistic regression used with case-control mother/offspring pairs and the log-linear regression used with case-parent triads. We evaluated a real dataset consisting of maternal/offspring pairs with and without PE for incompatibility effects using the optimal analysis based on the results of the simulation study.We identified a single coding scheme for the incompatibility effect that was equally or more powerful than all of the alternative analysis models evaluated, regardless of the true underlying model for the incompatibility effect. In addition, the log-linear regression was more powerful than the logistic regression when the heritability was low, and more robust to adjustment for maternal or fetal effects. For the PE data, this analysis revealed three genes, lymphotoxin alpha (LTA), von Willebrand factor (VWF), and alpha 2 chain of type IV collagen (COL4A2) with possible incompatibility effects.The incompatibility model should be evaluated for complications of pregnancy, such as PE, where the genotypes of two individuals may contribute to the presence of disease.

SUBMITTER: Parimi N

PROVIDER: S-EPMC2474585 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia.

Parimi Neeta N Tromp Gerard G Kuivaniemi Helena H Nien Jyh Kae JK Gomez Ricardo R Romero Roberto R Goddard Katrina Ab KA

BMC medical genetics 20080703

<h4>Background</h4>In utero interactions between incompatible maternal and fetal genotypes are a potential mechanism for the onset or progression of pregnancy related diseases such as pre-eclampsia (PE). However, the optimal analytical approach and study design for evaluating incompatible maternal/offspring genotype combinations is unclear.<h4>Methods</h4>Using simulation, we estimated the type I error and power of incompatible maternal/offspring genotype models for two analytical approaches: lo ...[more]

PMID: 18598365

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Project description:BackgroundPreeclampsia (PE) is a serious hypertensive pregnancy disorder with a significant genetic component. Numerous genetic studies, including our own, have yielded many susceptibility genes from distinct functional groups. Additionally, transcriptome profiling of tissues at the maternal-fetal interface has likewise yielded many differentially expressed genes. Often there is little overlap between these two approaches, although genes identified in both approaches are significantly associated with PE. We have thus taken a novel integrative bioinformatics approach of analysing pathways common to the susceptibility genes and the PE transcriptome.MethodsUsing Illumina Human Ht12v4 and Wg6v3 BeadChips, transcriptome profiling was conducted on n = 65 normotensive and n = 60 PE decidua basalis tissues collected at delivery. The R software package libraries lumi and limma were used to preprocess transcript data for pathway analysis. Pathways were analysed and constructed using Pathway Studio. We examined ten candidate genes, which are from these functional groups: activin/inhibin signalling-ACVR1, ACVR1C, ACVR2A, INHA, INHBB; structural components-COL4A1, COL4A2 and M1 family aminopeptidases-ERAP1, ERAP2 and LNPEP.Results/conclusionMajor common regulators/targets of these susceptibility genes identified were AGT, IFNG, IL6, INHBA, SERPINE1, TGFB1 and VEGFA. The top two categories of pathways associated with the susceptibility genes, which were significantly altered in the PE decidual transcriptome, were apoptosis and cell signaling (p < 0.001). Thus, susceptibility genes from distinct functional groups share similar downstream pathways through common regulators/targets, some of which are altered in PE. This study contributes to a better understanding of how susceptibility genes may interact in the development of PE. With this knowledge, more targeted functional analyses of PE susceptibility genes in these key pathways can be performed to examine their contributions to the pathogenesis and severity of PE.

Dataset Information

Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia.

Publications

Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia.

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