Blood Levels of Glycated CD59 (GCD59) as a Novel Biomarker for Screening and Diagnosis of Gesta>onal Diabetes Mellitus

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1 Blood Levels of Glycated CD59 (GCD59) as a Novel Biomarker for Screening and Diagnosis of P. Ghosh 1, M. A. Luque- Fernandez 4, A. Vaidya 2, M. Chorev 1, C. Zera 3, T. McElrath 3, M. Williams 4, E. Seely 2, J. Halperin 1 1 Divs. of Hematology, 2 Endocrinology and 3 Maternal Fetal Medicine, Brigham & Women s Hospital. 4 Harvard School of Public Health. Boston, MA

2 JAH and MC are founders and have financial interest in Mellitus LLC. Mellitus had licensed IP used in this research and has interests in developing diagnos=c tools for diabetes. These interests were reviewed and are managed by Brigham and Women s Hospital and Partners HealthCare in accordance with their conflict of interest policies.

3 GestaHonal Diabetes Mellitus (GDM) is a major cause of abnormal pregnancy outcomes. Pregnant women are currently screened for GDM using cumbersome glucose load methodologies. Experimental and clinical evidence supports a strong link between inachvahon of the complement regulatory protein CD59 by glycahon (forming glycated CD59 [GCD59]) and the pathogenesis of diabetes complicahons (reviewed in Endocrine Reviews 36 (3) 2015) We present the results of a study of plasma GCD59 levels in pregnant women undergoing two- step screening for GDM.

4 Blood Levels of Glycated CD59 (GCD59) as a Novel Biomarker for Screening and Diagnosis of Gesta>onal Diabetes Mellitus CD59 CD59 GCD59 CD59 is a cell membrane protein inhibitor of complement. A glycation motif (K41 and H44) makes human CD59 sensitive to inactivation by glycation (PNAS 2000). CD59 and GCD59 shedoff cell membranes are present in blood. ELISA to measure GCD59 in human fluids (AJH 2013) Capture mab CD59.! Detection mab A capture and a detection mab were raised using synthetic peptides (the detection antigen carried a pre-formed Lys[Nε-glucitol] lysine ). A surrogate CD59 linking both peptide antigens was used for calibration. The figures shows a typical assay calibration curve. Human studies showed higher levels of GCD59 in individuals with diabetes (JCEM 2014).

5 To inves>gate if blood levels of GCD59 in the late second trimester classify pregnant women with and without abnormal glucose tolerance and GDM. Methods Ø Nested case-control study of plasma GCD59 levels in 1000 pregnant women undergoing twostep screening for GDM in the late second trimester (gestational weeks 24-28) Ø STEP 1: 50gr-1-hr Glucose Load Test (GLT): Normal: <140 mg/dl. Failed: 140 mg/dl. STEP 2: 100gr-3-hr Oral Glucose Tolerance Test (OGTT): Normal (OGTT-N): All 4 values normal (Coustan & Carpenter). Impaired glucose tolerance (IGT): 1 abnormal value. GDM: at least 2 abnormal values. Ø Analysis: Subjects characteristics were described by case-control (Table 1). Ø The GCD59 distributions were described by case-control status: Normal GLT vs. failed GLT or Normal GLT vs. GDM. Ø GCD59 mean differences among groups were assessed using parametric tests. Ø GCD59 accuracy was assessed by ROC curves adjusted for maternal age, race and early pregnancy BMI. Ø The association between large for gestational age (LGA) prevalence and GCD59, was assessed using gender and age adjusted infant birth weight z-scores derived from the latest reference curves for the US population. LGA was defined as z-score 2.

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10 Pregnant women are screened for GDM using cumbersome glucose load methodologies that dichotomously classify them as normal or abnormal failing to capture the continuous association between maternal hyperglycemia and adverse pregnancy outcomes. Our study shows that a one time measurement of GCD59 in the late second trimester classified women with or without GDM as well as women with normal or failed GLT with high sensitivity and specificity. Importantly, higher levels of maternal GCD59 were associated with higher incidence of LGA newborns. We conclude that blood levels of GCD59 in the late second trimester represent a promising new biomarker for screening and diagnosis of pregnancy induced abnormal glucose tolerance and GDM. Funded by NIH grants: DK095429, DK and DK101442