STOX2 but not STOX1 is differentially expressed in decidua from pre-eclamptic women: data from the Second Nord-Trondelag Health Study

Fenstad, Mona Høysæter; Johnson, Matthew P.; Løset, Mari; Mundal, Siv Boon; Roten, Linda Tømmerdal; Eide, Irina P.; Bjørge, Line; Sande, Ragnar Kvie; Johansson, Åsa; Dyer, Thomas D.; Forsmo, Siri; Blangero, John; Moses, Eric K.; Austgulen, Rigmor

doi:10.1093/molehr/gaq064

Cited by 28 publications

(26 citation statements)

References 55 publications

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“…Interestingly, the third-ranked DMR genome-wide (Additional file 1: Figure S1) was located in the first intron of C9orf3 (chr9:97,504,001–97,504,500), which has been associated with polycystic ovary syndrome in women [34] and development of erectile dysfunction after radiotherapy for prostate cancer in men [35]. Another signal within this list was located in intron 1 of STOX2 (chr4:184,814,001–184,814,500), whose reduced expression has been implicated in pre-eclampsia [36]. Since adverse perinatal outcomes may be associated with maternal age, we further adjusted for this covariate and observed that the 46 FDR 25% WBC IVF-DMRs remained significant (Table 2).…”

Section: Resultsmentioning

confidence: 99%

DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation

et al. 2017

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BackgroundThe association of in vitro fertilisation (IVF) and DNA methylation has been studied predominantly at regulatory regions of imprinted genes and at just thousands of the ~28 million CpG sites in the human genome.MethodsWe investigated the links between IVF and DNA methylation patterns in whole cord blood cells (n = 98) and cord blood mononuclear cells (n = 82) from newborn twins using genome-wide methylated DNA immunoprecipitation coupled with deep sequencing.ResultsAt a false discovery rate (FDR) of 5%, we identified one significant whole blood DNA methylation change linked to conception via IVF, which was located ~3 kb upstream of TNP1, a gene previously linked to male infertility. The 46 most strongly associated signals (FDR of 25%) included a second region in a gene also previously linked to infertility, C9orf3, suggesting that our findings may in part capture the effect of parental subfertility. Using twin modelling, we observed that individual-specific environmental factors appear to be the main overall contributors of methylation variability at the FDR 25% IVF-associated differentially methylated regions, although evidence for methylation heritability was also obtained at several of these regions. We replicated previous findings of differential methylation associated with IVF at the H19/IGF2 region in cord blood mononuclear cells, and we validated the signal at C9orf3 in monozygotic twins. We also explored the impact of intracytoplasmic sperm injection on the FDR 25% signals for potential effects specific to male or female infertility factors.ConclusionsTo our knowledge, this is the most comprehensive study of DNA methylation profiles at birth and IVF conception to date, and our results show evidence for epigenetic modifications that may in part reflect parental subfertility.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0413-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation

et al. 2017

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“…Transcriptional profiling was performed on decidua basalis tissues from 37 cases and 58 controls using Illumina Human-6 v.2 Expression BeadChip (Illumina, San Diego, CA, USA) according to Illumina's standard protocols. The sample preparation has been described previously, 11,14 and the data set is available at ArrayExpress (http://www.ebi.ac. uk/microarray-as/ae/) (accession code E-TABM-682).…”

Section: Methodsmentioning

confidence: 99%

Identification of ACOX2 as a shared genetic risk factor for preeclampsia and cardiovascular disease

et al. 2011

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Preeclampsia (PE) is a serious complication of pregnancy, which is highly correlated with later life cardiovascular disease (CVD). Many risk factors are common for both diseases, but the contribution of shared genes remains to be determined. In this study, we used an integrative strategy to assess lipid traits as risk factors for PE and CVD by whole genome transcriptional profiling performed on Norwegian decidua basalis tissues (N¼95) from preeclamptic and normal pregnancies and on blood lymphocytes (N¼1240) from the San Antonio Family Heart Study (SAFHS). Among 222 genes that were differentially expressed (false discovery rate (FDR) P-value o0.05) between the PE, cases and controls, we found one gene, ACOX2 (acyl-coenzyme A oxidase 2, branched chain), that was downregulated in PE whose transcription was also inversely correlated with triglyceride levels (P¼5.6Â10 À7 ; FDR P-value¼0.0002) in SAFHS. We further report associations between SNPs in the ACOX2 gene and the transcription level (P-value¼0.0045) of the gene, as well as with triglyceride levels (P-value¼0.0051). ACOX2 is involved in bile acid production, a process that has been associated with both oxidative stress and regulation of triglyceride levels. Oxidative stress and increased triglyceride levels are known risk factors for CVD and both have also been associated with PE. Our results suggest that downregulation of ACOX2 is a shared risk factor for PE and CVD.

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“…PE was defined as persistent hypertension (blood pressure of ≥140/90 mmHg) plus proteinuria (≥0.3 g/day or ≥1+ according to a dipstick test), developing after 20 weeks of pregnancy (Gifford et al 2000). Descriptive characteristics can be found in Table 1 and information about the study population has been published previously (Fenstad et al 2010; Løset et al 2010). Women with preeclamptic pregnancies ( N = 37) had cesarean section performed for medical indications, and none of them were in labor prior to cesarean section.…”

Section: Methodsmentioning

confidence: 99%

Partial correlation network analyses to detect altered gene interactions in human disease: using preeclampsia as a model

et al. 2010

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Differences in gene expression between cases and controls have been identified for a number of human diseases. However, the underlying mechanisms of transcriptional regulation remain largely unknown. Beyond comparisons of absolute or relative expression levels, disease states may be associated with alterations in the observed correlational patterns among sets of genes. Here we use partial correlation networks aiming to compare the transcriptional co-regulation for 222 genes that are differentially expressed in decidual tissues between preeclampsia (PE) cases and non-PE controls. Partial correlation coefficients (PCCs) have been calculated in cases (N = 37) and controls (N = 58) separately. For all PCCs, we tested if they were significant non-zero in the cases and controls separately. In addition, to examine if a given PCC is different between the cases and controls, we tested if the difference between two PCCs were significant non-zero. In the group with PE cases, only five PCCs were significant (FDR p value ≤ 0.05), of which none were significantly different from the PCCs in the controls. However, in the controls we identified a total of 56 statistically significant PCCs (FDR p value ≤ 0.05), of which 31 were also significantly different (FDR p value ≤ 0.05) from the PCCs in the PE cases. The identified partial correlation networks included genes that are potentially relevant for developing PE, including both known susceptibility genes (EGFL7, HES1) and novel candidate genes (CFH, NADSYN1, DBP, FIGLA). Our results might suggest that disturbed interactions, or higher order relationships between these genes play an important role in developing the disease.

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STOX2 but not STOX1 is differentially expressed in decidua from pre-eclamptic women: data from the Second Nord-Trondelag Health Study

Cited by 28 publications

References 55 publications

DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation

DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation

Identification of ACOX2 as a shared genetic risk factor for preeclampsia and cardiovascular disease

Partial correlation network analyses to detect altered gene interactions in human disease: using preeclampsia as a model

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