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Circulating Growth Differentiation Factor 15 Is Increased Preceding Preeclampsia Diagnosis: Implications as a Disease Biomarker.

ABSTRACT: Background We investigated the biomarker potential of growth differentiation factor 15 (GDF-15), a stress response protein highly expressed in placenta, to predict preeclampsia. Methods and Results In 2 prospective cohorts (cohort 1: 960 controls, 39 women who developed preeclampsia; cohort 2: 950 controls, 41 developed preeclampsia), plasma concentrations of GDF-15 at 36 weeks' gestation were significantly increased among those who developed preeclampsia (P<0.001), area under the receiver operating characteristic curves (AUC) of 0.66 and 0.71, respectively. In cohort 2 a ratio of sFlt-1/PlGF (a clinical biomarker for preeclampsia) had a sensitivity of 61.0% at 83.2% specificity to predict those who will develop preeclampsia (AUC of 0.79). A ratio of GDF-15×sFlt-1/PlGF yielded a sensitivity of 68.3% at 83.2% specificity (AUC of 0.82). GDF-15 was consistently elevated across a number of international cohorts: levels were higher in placenta and blood from women delivering <34 weeks' gestation due to preterm preeclampsia in Melbourne, Australia; and in the blood at 26 to 32 weeks' gestation among 57 women attending the Manchester Antenatal Vascular Service (MAViS, UK) who developed preeclampsia (P=0.0002), compared with 176 controls. In the Preeclampsia Obstetric adVerse Events biobank (PROVE, South Africa), plasma GDF-15 was significantly increased in women with preeclampsia with severe features (P=0.02; n=14) compared to controls (n=14). Conclusions We conclude circulating GDF-15 is elevated among women more likely to develop preeclampsia or diagnosed with the condition. It may have value as a clinical biomarker, including the potential to improve the sensitivity of sFlt-1/PlGF ratio.

SUBMITTER: Cruickshank T

PROVIDER: S-EPMC8475051 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Circulating Growth Differentiation Factor 15 Is Increased Preceding Preeclampsia Diagnosis: Implications as a Disease Biomarker.

Cruickshank Tess T MacDonald Teresa M TM Walker Susan P SP Keenan Emerson E Dane Kirsten K Middleton Anna A Kyritsis Valerie V Myers Jenny J Cluver Catherine C Hastie Roxanne R Bergman Lina L Garcha Damanpreet D Cannon Ping P Murray Elizabeth E Nguyen Tuong-Vi TV Hiscock Richard R Pritchard Natasha N Hannan Natalie J NJ Tong Stephen S Kaitu'u-Lino Tu'uhevaha J TJ

Journal of the American Heart Association 20210813 16

Background We investigated the biomarker potential of growth differentiation factor 15 (GDF-15), a stress response protein highly expressed in placenta, to predict preeclampsia. Methods and Results In 2 prospective cohorts (cohort 1: 960 controls, 39 women who developed preeclampsia; cohort 2: 950 controls, 41 developed preeclampsia), plasma concentrations of GDF-15 at 36 weeks' gestation were significantly increased among those who developed preeclampsia (<i>P</i><0.001), area under the receive ...[more]

PMID: 34387117

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Project description:BackgroundGrowth Differentiation Factor 15 (GDF15), a nonspecific inflammatory marker and member of the TGF-β superfamily, has a well-established role in both inflammation and metabolic modulation, but lacks a comprehensive paediatric literature review. In several adult disease states, including cancer cachexia and pregnancy, circulation and expression of GDF15 has been of clinical and scientific interest, but little published paediatric data exists. As such, we aim to summarize existing paediatric studies.MethodsThis review follows the PRISMA-ScR guidelines for reporting and aims to summarize existing paediatric studies including GDF15, describe disease entities in which GDF15 has been investigated including existing reference ranges, and identify literature gaps to present future clinical and research direction. Our search strategy queried Ovid MEDLINE, Ovid Embase, Cochrane Library and Scopus databases to find original scientific articles measuring GDF15 from birth through children up to age 18. Data relating to study participant demographic and disease pathology, GDF15 measurement methods and clinical outcomes of interest were extracted.ResultsSixty-two studies were included, classified as cardiac, endocrine, mitochondrial, hematologic, neonatal, oncologic, infectious, rheumatologic, renal, neurologic or healthy. While several entities demonstrated elevated GDF15, the highest median GDF15 levels were observed in cardiac arrest 7089 pg/mL (interquartile range 3805-13 306) and mitochondrial diseases 4640 pg/mL (1896-14 064). In certain conditions, including cardiac stress, polycystic ovarian syndrome (PCOS), Kawasaki Disease (KD) and certain mitochondrial myopathies GDF15 can normalize with disease treatment or resolution. Of healthy children studied, GDF15 levels were highest in healthy neonates and followed a predictable pattern, decreasing over time. Mean and standard deviation values of GDF15 in healthy children were 343.8 ± 221.0 pg/mL, with a range of 90-1134 pg/mL for study averages.ConclusionsCirculating GDF15 has been studied in a variety of paediatric diseases. However, variable evaluated outcome measures and GDF15 measurement methodologies prevent generalizability and direct comparison of these published studies. Validating normal GDF15 levels in children with standardized and reproducible methodology will help clarify GDF15's utility as a diagnostic marker of disease, a necessary step to elucidate clinical implications of GDF15 over expression and its potential as a therapeutic target.

Project description:BackgroundPreeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction.MethodsPlasma samples and placentas were collected from uncomplicated and preeclampsia pregnancies. Uncomplicated placentas and trophoblast cells (BeWo) were exposed to hypoxia. The reactive dicarbonyl MGO and advanced glycation end products (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL], and MGO-derived hydroimidazolone [MG-H]) were quantified using liquid chromatography-tandem mass spectrometry. The activity of GLO1 (glyoxalase-1), that is, the enzyme detoxifying MGO, was measured. The impact of MGO on vascular function was evaluated using wire/pressure myography. The therapeutic potential of the MGO-quencher quercetin and mitochondrial-specific antioxidant mitoquinone mesylate (MitoQ) was explored.ResultsMGO, CML, CEL, and MG-H2 levels were elevated in preeclampsia-placentas (+36%, +36%, +25%, and +22%, respectively). Reduced GLO1 activity was observed in preeclampsia-placentas (-12%) and hypoxia-exposed placentas (-16%). Hypoxia-induced MGO accumulation in placentas was mitigated by the MGO-quencher quercetin. Trophoblast cells were identified as the primary source of MGO. Reduced GLO1 activity was also observed in hypoxia-exposed BeWo cells (-26%). Maternal plasma concentrations of CML and the MGO-derived MG-H1 increased as early as 12 weeks of gestation (+16% and +17%, respectively). MGO impaired endothelial barrier function, an effect mitigated by MitoQ, and heightened vascular responsiveness to thromboxane A2.ConclusionsThis study reveals the accumulation of placental MGO in preeclampsia and upon exposure to hypoxia, demonstrates how MGO can contribute to vascular impairment, and highlights plasma CML and MG-H1 levels as promising early biomarkers for preeclampsia.

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Circulating Growth Differentiation Factor 15 Is Increased Preceding Preeclampsia Diagnosis: Implications as a Disease Biomarker.

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Circulating Growth Differentiation Factor 15 Is Increased Preceding Preeclampsia Diagnosis: Implications as a Disease Biomarker.

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