Dataset Information

Genetic association of ERAP1 and ERAP2 with eclampsia and preeclampsia in northeastern Brazilian women.

ABSTRACT: The clinical spectrum of hypertensive disorders of pregnancy (HDP) is determined by the interplay between environmental and genetic factors, most of which remains unknown. ERAP1, ERAP2 and LNPEP genes code for multifunctional aminopeptidases involved with antigen processing and degradation of small peptides such as angiotensin II (Ang II), vasopressin and oxytocin. We aimed to test for associations between genetic variants in aminopeptidases and HDP. A total of 1282 pregnant women (normotensive controls, n = 693; preeclampsia, n = 342; chronic hypertension with superimposed preeclampsia, n = 61; eclampsia, n = 74; and HELLP syndrome, n = 112) were genotyped for variants in LNPEP (rs27300, rs38034, rs2303138), ERAP1 (rs27044, rs30187) and ERAP2 (rs2549796 rs2927609 rs11135484). We also evaluated the effect of ERAP1 rs30187 on plasma Ang II levels in an additional cohort of 65 pregnant women. The genotype C/C, in ERAP1 rs30187 variant (c.1583 T > C, p.Lys528Arg), was associated with increased risk of eclampsia (OR = 1.85, p = 0.019) whereas ERAP2 haplotype rs2549796(C)-rs2927609(C)-rs11135484(G) was associated with preeclampsia (OR = 1.96, corrected p-value = 0.01). Ang II plasma levels did not differ across rs30187 genotypic groups (p = 0.895). In conclusion, ERAP1 gene is associated with eclampsia whereas ERAP2 is associated with preeclampsia, although the mechanism by which genetic variants in ERAPs influence the risk of preeclampsia and eclampsia remain to be elucidated.

SUBMITTER: Ferreira LC

PROVIDER: S-EPMC7990956 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Genetic association of ERAP1 and ERAP2 with eclampsia and preeclampsia in northeastern Brazilian women.

Ferreira Leonardo Capistrano LC Gomes Carlos Eduardo Maia CEM Duggal Priya P De Paula Holanda Ingrid I de Lima Amanda Samara AS do Nascimento Paulo Ricardo Porfírio PRP Jeronimo Selma Maria Bezerra SMB

Scientific reports 20210324 1

The clinical spectrum of hypertensive disorders of pregnancy (HDP) is determined by the interplay between environmental and genetic factors, most of which remains unknown. ERAP1, ERAP2 and LNPEP genes code for multifunctional aminopeptidases involved with antigen processing and degradation of small peptides such as angiotensin II (Ang II), vasopressin and oxytocin. We aimed to test for associations between genetic variants in aminopeptidases and HDP. A total of 1282 pregnant women (normotensive ...[more]

PMID: 33762660

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Project description:Pre-eclampsia (PE) is a disorder of pregnancy, often leading to serious and fatal complications. Endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1/ERAP2) are present in the placenta. They are involved in processes regulating blood pressure, angiogenesis, cytokine receptor shedding, and immune recognition. Previous studies have associated both ERAP1/ERAP2 genetic variants with PE, although the underlying mechanisms remain unknown. Less is known about the roles for these enzymes in early placentation, which could be a contributory factor to PE. To ascertain whether ERAP1/ERAP2 change in PE and whether such a change is present before PE is clinically diagnosed, we analyzed mRNA and ERAP1/2 protein expression in the placenta in the early first trimester (8-14 weeks) and at delivery in normotensive or PE women (n = 12/group). Gene expression was analyzed using qPCR, and protein expression and localization were assessed by immunohistochemistry. Additionally, we profiled peripheral immune cells from normotensive and PE (n = 5/group) women for activation and expression of cytotoxic markers using flow cytometry to investigate a possible correlation with placental expression of ERAP1/2. Finally, we characterized the cytokines released from immune cells isolated from normotensive women and those with PE, stimulated ex vivo by JEG-3 trophoblast cells. The ERAP1 protein was significantly upregulated in first trimester placentae compared to placentae at delivery from both normotensive and PE women (p < 0.05): expression of placental ERAP1 protein was also relatively higher in normotensive than PE women. Although the protein expression of both ERAP1/ERAP2 was significantly lower in women with PE compared to normotensive controls (p < 0.05), ERAP2 protein expression remained unchanged in normotensive women at delivery compared to expression in the first trimester. Flow cytometry analysis revealed an increase in activation and cytotoxic natural killer (NK) cells in peripheral blood of PE compared to normotensive women. Intriguingly, there was a notable difference in cytokine release from the activated immune cells when further stimulated by trophoblast cells. The immune cells from PE released elevated expressions of interleukin (IL)-2, IL-4, and most notably, pro-inflammatory IL-13 and IL-17?, inflammatory cytokines tumor necrosis factor (TNF)-? and interferon (IFN)-?, and granulocyte-macrophage colony-stimulating factor (GM-CSF) compared to normal peripheral blood mononuclear cells (PBMCs). Taken together, these findings suggest that differential lymphocyte activation could be associated with altered ERAP1/ERAP2 expression.

Project description:BackgroundPreeclampsia/eclampsia is a major cause of maternal morbidity and mortality worldwide, yet patients' perspectives about their diagnosis are not well understood. Our study examines patient knowledge among women with preeclampsia/eclampsia in a large urban hospital in Ghana.MethodsPostpartum women diagnosed with preeclampsia or eclampsia were asked to complete a survey 2-5 days after delivery that assessed demographic information, key obstetric factors, and questions regarding provider counseling. Provider counseling on diagnosis, causes, complications, and future health effects of preeclampsia/eclampsia was quantified on a 4-point scale ('Counseling Composite Score'). Participants also completed an objective knowledge assessment regarding preeclampsia/eclampsia, scored from 0 to 22 points ('Preeclampsia/Eclampsia Knowledge Score' (PEKS)). Linear regression was used to identify predictors of knowledge score.ResultsA total of 150 participants were recruited, 88.7% (133) with preeclampsia and 11.3% (17) with eclampsia. Participants had a median age of 32 years, median parity of 2, and mean number of 5.4 antenatal visits. Approximately half of participants reported primary education as their highest level of education. While 74% of women reported having a complication during pregnancy, only 32% of participants with preeclampsia were able to correctly identify their diagnosis, and no participants diagnosed with eclampsia could correctly identify their diagnosis. Thirty-one percent of participants reported receiving no counseling from providers, and only 11% received counseling in all four categories. Even when counseled, 40-50% of participants reported incomplete understanding. Out of 22 possible points on a cumulative knowledge assessment scale, participants had a mean score of 12.9 ± 0.38. Adjusting for age, parity, and the number of antenatal visits, higher scores on the knowledge assessment are associated with more provider counseling (β 1.4, SE 0.3, p < 0.001) and higher level of education (β 1.3, SE 0.48, p = 0.008).ConclusionsCounseling by healthcare providers is associated with higher performance on a knowledge assessment about preeclampsia/eclampsia. Patient knowledge about preeclampsia/eclampsia is important for efforts to encourage informed healthcare decisions, promote early antenatal care, and improve self-recognition of warning signs-ultimately improving morbidity and reducing mortality.

Dataset Information

Genetic association of ERAP1 and ERAP2 with eclampsia and preeclampsia in northeastern Brazilian women.

Publications

Genetic association of ERAP1 and ERAP2 with eclampsia and preeclampsia in northeastern Brazilian women.

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