Research Article The Immunosignature of Mother/Fetus Couples in Gestational Diabetes Mellitus: Role of HLA-G 14bp ins/del and PAPP-A A/C Polymorphisms in the Uterine Inflammatory Milieu Miryam Martinetti, 1 Fausta Beneventi, 2 Cristina Capittini, 3 Elena Locatelli, 2 Margherita Simonetta, 2 Chiara Cavagnoli, 2 Irene De Maggio, 2 Annalisa De Silvestri, 3 Annamaria Pasi, 1 and Arsenio Spinillo 2 1 Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Policlinico San Matteo Foundation, Pavia, Italy 2 Department of Obstetrics and Gynecology, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy 3 Clinical Epidemiology and Biometric Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy Correspondence should be addressed to Cristina Capittini; c.capittini@smatteo.pv.it Received 22 February 2017; Revised 6 April 2017; Accepted 23 April 2017; Published 1 June 2017 Academic Editor: Alvaro González Copyright © 2017 Miryam Martinetti et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We enrolled 151 healthy mother/newborn couples and 26 with gestational diabetes mellitus (GDM). HLA-G and PAPP-A plasma levels were measured by ELISA at first and second trimesters, at delivery, and in cord blood. HLA-G 14 bp ins/del and PAPP-A A/C polymorphisms were genotyped. HLA-G del/del and PAPP-A C/C genotypes were more frequent among GDM mothers than controls. We observed a genetic epistasis between the two polymorphisms: the HLA-G del/del and PAPP-A C/C combination was carried by 8% of GDM mothers and 1.3% of controls (OR = 9.5, 95% CI = 0.8–109, p =0 07). GDM mothers showed increased sHLA-G levels compared to controls (p =0 004), and those carrying the HLA-G del/del genotype produced more sHLA-G at the second trimester and at delivery (p =0 014). A genetic pressure by fetal genotype on maternal sHLA-G production was observed in GDM mothers with heterozygous HLA-G del/ins newborns (p =0 02). Babies born to GDM mothers showed higher sHLA-G concentrations compared to those born to healthy mothers, and those carrying HLA-G del/del showed the highest sHLA-G levels (p =0 013). PAPP-A amounts significantly increased along pregnancy (p <0 001), but the median levels at the first and second trimesters were significantly lower in GDM (p =0 03). Our findings first suggest an involvement of HLA-G and PAPP-A gene-protein interaction in GDM and highlight a possible contribution of the fetus in balancing maternal inflammation. 1. Introduction Gestational diabetes mellitus (GDM) is a pregnancy-related complication defined as glucose intolerance associated to maternal decreased insulin sensitivity and increased insulin resistance [1]. Even though the pathophysiologic mecha- nisms underlying GDM are still unknown, the placenta in GDM women shows abnormal structural changes causing immature villous structure and hypervascularization and dis- turbances in intervillous circulation. If not properly diag- nosed and treated, GDM can determine the occurrence of various complications, both in the mother and fetus [2]. In early pregnancy, two proteins are important in pro- moting decidual vascularization: the nonclassical human leu- kocyte antigen- (HLA-) G class I molecule and the pregnancy-associated plasma protein A (PAPP-A). HLA-G can stimulate the production of angiogenic factors and cyto- kines that favor embryo implantation, placental vasculariza- tion, and maternal-fetal tolerance [3]. PAPP-A is a metalloproteinase secreted by syncytiotrophoblast with pro- teolytic activity against insulin-like growth factor-binding protein-4, an important regulator of insulin growth factor bioavailability that plays a central role in fetal development and maternal well-being [4]. Hindawi Disease Markers Volume 2017, Article ID 4254750, 12 pages https://doi.org/10.1155/2017/4254750