Collaboration to Understand Complex Diseases

Roberts, James M.; Mascalzoni, Deborah; Ness, Roberta B.; Poston, Lucilla

doi:10.1161/hypertensionaha.115.06133

Cited by 36 publications

(21 citation statements)

References 23 publications

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“…Next, we measured 5 mC to quantify global DNA methylation levels in E18. 5 Figure 1A. As a result of these matings, half of the placentas are ADA deficient and half are ADA positive (heterozygous for the null allele).…”

Section: Mice With Elevated Placental Adenosine Display Global Placenmentioning

confidence: 99%

“…[1][2][3][4][5] The condition affects ≈8% of first pregnancies and accounts for >80 000 premature births each year in the United States (≈15% of total premature births), >$4 billion in medical costs, and immeasurable human suffering. Preeclampsia adversely affects the mother's kidneys, heart, liver, and other vital organs and, if undetected or untreated, can lead to seizures (eclampsia), cerebral hemorrhage, failure in vital organs (eg, kidney and heart), and death.…”

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confidence: 99%

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Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia

Huang

Iriyama

et al. 2017

Hypertension

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Consistent with this, detailed analysis of DNA from preeclampsia placentas showed that hypomethylation at specific promoter regions was associated with increased expression of specific genes that may contribute to the pathophysiology of Abstract-Preeclampsia is a prevalent pregnancy hypertensive disease with both maternal and fetal morbidity and mortality.Emerging evidence indicates that global placental DNA hypomethylation is observed in patients with preeclampsia and is linked to altered gene expression and disease development. However, the molecular basis underlying placental epigenetic changes in preeclampsia remains unclear. Using 2 independent experimental models of preeclampsia, adenosine deaminase-deficient mice and a pathogenic autoantibody-induced mouse model of preeclampsia, we demonstrate that elevated placental adenosine not only induces hallmark features of preeclampsia but also causes placental DNA hypomethylation. The use of genetic approaches to express an adenosine deaminase minigene specifically in placentas, or adenosine deaminase enzyme replacement therapy, restored placental adenosine to normal levels, attenuated preeclampsia features, and abolished placental DNA hypomethylation in adenosine deaminase-deficient mice. Genetic deletion of CD73 (an ectonucleotidase that converts AMP to adenosine) prevented the elevation of placental adenosine in the autoantibodyinduced preeclampsia mouse model and ameliorated preeclampsia features and placental DNA hypomethylation.Immunohistochemical studies revealed that elevated placental adenosine-mediated DNA hypomethylation predominantly occurs in spongiotrophoblasts and labyrinthine trophoblasts and that this effect is independent of A2B adenosine receptor activation in both preeclampsia models. Extending our mouse findings to humans, we used cultured human trophoblasts to demonstrate that adenosine functions intracellularly and induces DNA hypomethylation without A2B adenosine receptor activation. Altogether, both mouse and human studies reveal novel mechanisms underlying placental DNA hypomethylation and potential therapeutic approaches for preeclampsia. (Hypertension. 2017;70:209-218.

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Section: Mice With Elevated Placental Adenosine Display Global Placenmentioning

confidence: 99%

mentioning

confidence: 99%

Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia

Huang

Iriyama

et al. 2017

Hypertension

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“…Six hundred PE women, 600 affected fetuses and 600 healthy pregnant control women from the FINNPEC cohort were included in the follow-up genotyping after the genome-wide association screening was performed in the discovery cohorts. FINNPEC also participates in the Global Pregnancy Collaboration (CoLab), a major Bill and Melinda Gates Foundation supported initiative focused on adverse pregnancy outcomes and achieving a better understanding of their causes 29. CoLab is the largest international initiative until now to understand major pregnancy disorders in a global setting.…”

Section: Findings Until Nowmentioning

confidence: 99%

Cohort profile: the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC)

et al. 2016

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PurposeThe Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) Study was established to set up a nationwide clinical and DNA database on women with and without pre-eclampsia (PE), including their partners and infants, in order to identify genetic risk factors for PE.ParticipantsFINNPEC is a cross-sectional case–control cohort collected from 5 university hospitals in Finland during 2008–2011. A total of 1450 patients with PE and 1065 pregnant control women without PE (aged 18–47 years) were recruited. Altogether, there were 1377 full triads (625 PE and 752 control triads).Findings to dateThe established cohort holds both clinical and genetic information of mother–infant–father triads representing a valuable resource for studying the pathogenesis of the disease. Furthermore, maternal biological samples (first and third trimester serum and placenta) will provide additional information for PE research. Until now, research has encompassed studies on candidate genes, Sanger and next-generation sequencing, and various studies on the placenta. FINNPEC has also participated in the InterPregGen study, which is the largest investigation on maternal and fetal genetic factors underlying PE until now.Future plansOngoing studies focus on elucidating the role of immunogenetic and metabolic factors in PE. Data on morbidity and mortality will be collected from mothers and fathers through links to the nationwide health registers.

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“…Similar initiatives are found in Brazil (66). Due to the heterogeneity of the samples and different collection strategies of existing biobanks, adequate skills training, capacity-building of LMICbased researchers, and regulatory environments would need to be in place to support standardization of biobanks globally (63), as well as the infrastructure (such as 24-h electricity) for sample storage.…”

Section: Lmic-based Data Repositories and Biobanksmentioning

confidence: 91%

Cardiometabolic Risk Factors in Pregnancy and Implications for Long-Term Health: Identifying the Research Priorities for Low-Resource Settings

Nagraj

Kennedy

Norton

et al. 2020

Front. Cardiovasc. Med.

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Cardiometabolic disorders (CMDs), including ischemic heart disease, stroke and type 2 diabetes are the leading causes of mortality and morbidity in women worldwide. The burden of CMDs falls disproportionately on low and middle-income countries (LMICs), placing substantial demands on already pressured health systems. Cardiometabolic disorders may present up to a decade earlier in some LMIC settings, and are associated with high-case fatality rates. Early identification and ongoing postpartum follow-up of women with pregnancy complications such as hypertensive disorders of pregnancy (HDPs), and gestational diabetes mellitus (GDM) may offer opportunities for prevention, or help delay onset of CMDs. This mini-review paper presents an overview of the key challenges faced in the early identification, referral and management of pregnant women at increased risk of CMDs, in low-resource settings worldwide. Evidence-based strategies, including novel diagnostics, technology and innovations for early detection, screening and management for pregnant women at high-risk of CMDs are presented. The review highlights the key research priorities for addressing cardiometabolic risk in pregnancy in low-resource settings.

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Collaboration to Understand Complex Diseases

Cited by 36 publications

References 23 publications

Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia

Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia

Cohort profile: the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC)

Cardiometabolic Risk Factors in Pregnancy and Implications for Long-Term Health: Identifying the Research Priorities for Low-Resource Settings

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