? The goal of this proposal is to validate glycated CD59 (GCD59) in human blood as a novel biomarker to screen for studies of pregnancy-induced glucose intolerance. This proposal is highly translational and addresses major Public Health priorities because: 1) women with pregnancy-induced glucose intolerance and their fetus are at an increased risk of adverse clinical outcomes and perinatal complications, 2) the frequency of pregnancy-induced glucose intolerance is increasing at alarming rates, 3) epidemiological studies have shown that appropriate treatment reduces the associated risks for the mother and newborn, and 4) the glucose load tests, currently the gold standard identifying pregnancy-induced glucose intolerance, are expensive, time consuming, non-physiologic and unpleasant, have poor reproducibility on repeat testing. These facts highlight why there is agreement that a simpler, shorter, easier-to-use, cost-effective, sensitive and specific test would be a much better tool to screen for pregnancy-induced glucose intolerance. The applicants have 1) discovered that human CD59 is inactivated by glycation, 2) provided evidence for a link between the complement system and the pathogenesis of the complications of diabetes, and 3) developed key reagents and established a specific and sensitive assay that allows quantification of GCD59 in blood. With this assay, we have conducted pilot studies in pregnant women undergoing glucose- loading tests to screen for GDM. The results showed that a single measurement of plasma GCD59 at week ? 24-26 predicted pregnancy-induced glucose intolerance and GDM with high specificity and sensitivity (ROC AUC: 0.93). Based on these robust preliminary data and available resources, we now propose the highly focused aim of prospectively studying a large cohort of pregnant women to assess the utility of GCD59 as a simple, easy-to-use test for early prediction of pregnancy-induced glucose intolerance. All necessary tools and expertise to accomplish our aims are available in the laboratory of the applicant and expert collaborators, including monoclonal antibodies specific for GCD59 and assay calibrators, access to plasma samples from a large and diverse population of pregnant women undergoing standard of care screening for GDM, diagnostic tools, equipment and expertise necessary to conduct all studies proposed in the application. Successful accomplishment of our aim will provide a clinically useful and independent predictor to investigate pregnancy-induced glucose intolerance that could simplify the earlier screening and diagnosis of this condition.

Public Health Relevance

? This highly translational proposal (a) has as a main goal the validation of glycated CD59 (the glucose inactivated form of the key complement regulatory protein known as CD59) in human plasma (pGCD59), as a novel biomarker for early detection of pregnancy-induce glucose intolerance and gestational diabetes, (b) addresses major Public Health priorities, and (c) is based on a robust hypothesis, extensive preliminary data and availability of all assays/reagents needed. The relevance of the proposed studies is highlighted by the fact that Gestational Diabetes, which occurs at a progressively higher rate, is a major cause of maternal and fetal adverse pregnancy outcomes to the point that the current standard of care is to screen for this condition all pregnant women who do not have evidence of diabetes at first pre-natal care visit. Successful accomplishments of the project?s aims may potentially simplify screening and diagnosis of GDM, impact clinical practice globally, unite international guidelines and allow interventions aimed at reducing the incidence of abnormal outcomes caused by pregnancy-induced glucose intolerance.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Linder, Barbara
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Brigham and Women's Hospital
United States
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