Temporal Variation in Soluble Human Leukocyte Antigen-G (sHLA-G) and Pregnancy-Associated Plasma Protein A (PAPP-A) in Pregnancies Complicated by Gestational Diabetes Mellitus and in Controls
Corresponding Author
Fausta Beneventi
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, Pavia, Italy
Correspondence
Fausta Beneventi, Department of Obstetrics and Gynecology, IRCCS Fondazione Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy.
E-mails: [email protected];
Search for more papers by this authorMargherita Simonetta
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, Pavia, Italy
Search for more papers by this authorElena Locatelli
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, Pavia, Italy
Search for more papers by this authorChiara Cavagnoli
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, Pavia, Italy
Search for more papers by this authorCarla Badulli
Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorElisabetta Lovati
First Department of Medicine, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorGiulia Garbin
Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorEmilia Genini
Clinical Chemistry Laboratory, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorRiccardo Albertini
Clinical Chemistry Laboratory, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorCarmine Tinelli
Clinical Epidemiology and Biometric Unit, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorMiryam Martinetti
Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorArsenio Spinillo
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, Pavia, Italy
Search for more papers by this authorCorresponding Author
Fausta Beneventi
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, Pavia, Italy
Correspondence
Fausta Beneventi, Department of Obstetrics and Gynecology, IRCCS Fondazione Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy.
E-mails: [email protected];
Search for more papers by this authorMargherita Simonetta
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, Pavia, Italy
Search for more papers by this authorElena Locatelli
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, Pavia, Italy
Search for more papers by this authorChiara Cavagnoli
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, Pavia, Italy
Search for more papers by this authorCarla Badulli
Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorElisabetta Lovati
First Department of Medicine, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorGiulia Garbin
Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorEmilia Genini
Clinical Chemistry Laboratory, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorRiccardo Albertini
Clinical Chemistry Laboratory, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorCarmine Tinelli
Clinical Epidemiology and Biometric Unit, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorMiryam Martinetti
Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Search for more papers by this authorArsenio Spinillo
Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo and University of Pavia, Pavia, Italy
Search for more papers by this authorAbstract
Problem
To target gestational diabetes mellitus (GDM) by means of temporal variation in pregnancy-associated plasma protein A (PAPP-A) and soluble human leukocyte antigen-G (sHLA-G).
Method of study
Retrospective analysis of PAPP-A and sHLA-G blood levels in historical samples of 112 GDM and 112 controls, drawn at first trimester, and prospective study in 18 GDM and 105 controls collected in triplicate along the pregnancy. Six hundred and sixty-five samples were analyzed.
Results
Gestational diabetes mellitus had significantly lower first-trimester PAPP-A concentrations than controls (2343 ± 1519 versus 2996 ± 1955 mU/mL, in retrospective brunch and 2490.57 ± 1828.52 versus 3240.84 ± 1930.69 mU/L in prospective one, P < 0.001). First-trimester sHLA-G level was significantly lower in GDM than in controls (52.88 ± 59.69 versus 66.81 ± 50.14 ng/mL, P < 0.001) and increased during gestation in diabetic women showing an opposite trend with respect to the controls.
Conclusion
PAPP-A and sHLA-G are independent markers of GDM. Quantitative variations during pregnancy help to early unravel the onset of GDM.
References
- 1 American Diabetes Association: Diagnosis and classification of diabetes mellitus. Diabetes Care 2012; 35: S64–S71.
- 2Hiden U, Lassance L, Tabrizi NG, Miedl H, Tam-Amersdorfer C, Cetin I, Lang U, Desoye G: Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM)-associated up-regulation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto-placental endothelium. J Clin Endocrinol Metab 2012; 14: 3613–3621.
- 3Gauster M, Desoye G, Totsch M, Hiden U: The placenta and gestational diabetes mellitus. Curr Diab Rep 2012; 12: 16–23.
- 4Pérez-Pérez A, Maymó JL, Gambino YP, Guadix P, Dueñas JL, Varone CL, Sánchez-Margalet V: Activated translation signaling in placenta from pregnant women with gestational diabetes mellitus: possible role of leptin. Horm Metab Res 2013; 5: 436–442.
- 5Sun L, Jin Z, Teng W, Chi X, Zhang Y, Ai W, Wang P: SHBG in GDM maternal serum, placental tissues and umbilical cord serum expression changes and its significance. Diabetes Res Clin Pract 2013; 99: 168–173.
- 6Gomes CP, Torloni MR, Gueuvoghlanian-Silva BY, Alexandre SM, Mattar R, Daher S: Cytokine levels in gestational diabetes mellitus: a systematic review of the literature. Am J Reprod Immunol 2013; 69: 545–557.
- 7Rizzo R, Bortolotti D, Baricordi OR, Fainardi E: New insights into HLA-G and inflammatory diseases. Inflamm Allergy Drug Targets 2012; 11: 448–463.
- 8Resch ZT, Chen BK, Bale LK, Oxvig C, Overgaard MT, Conover CA: Pregnancy-associated plasma protein a gene expression as a target of inflammatory cytokines. Endocrinology 2004; 145: 1124–1129.
- 9Beneventi F, Simonetta M, Lovati E, Albonico G, Tinelli C, Locatelli E, Spinillo A: First trimester pregnancy-associated plasma protein-A in pregnancies complicated by subsequent gestational diabetes. Prenat Diagn 2011; 31: 523–528.
- 10Kirkegaard I, Uldbjerg N, Henriksen TB: PAPP-A and free beta-hCG in relation to admission to neonatal intensive care unit and neonatal disease. Prenat Diagn 2011; 31: 1169–1175.
- 11Roussev RG, Coulam CB: HLA-G and its role in implantation (review). J Assist Reprod Genet 2007; 24: 288–295.
- 12Christiansen OB: Reproductive immunology. Mol Immunol 2013; 55: 8–15.
- 13Cirulli V, Zalatan J, McMaster M, Prinsen R, Salomon DR, Ricordi C, Torbett BE, Meda P, Crisa L: The class I HLA repertoire of pancreatic islets comprises the nonclassical class ib antigen HLA-G. Diabetes 2006; 55: 1214–1222.
- 14Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R: A class I antigen, HLA-G, expressed in human trophoblasts. Science 1990; 248: 220–223.
- 15King A, Boocock C, Sharkey AM, Gardner L, Beretta A, Siccardi AG, Loke YW. Evidence for the expression of HLAA-C class I mRNA and protein by human first trimester trophoblast. J Immunol 1996; 156: 2068–2076.
- 16Carosella ED, Paul P, Moreau P, Rouas-Freiss N: HLA-G and HLA-E: fundamental and pathophysiological aspects. Immunol Today 2000; 21: 532–534.
- 17Paul P, Cabestre FA, Ibrahim EC, Lefebvre S, Khalil-Daher I, Vazeux G, Quiles RM, Bermond F, Dausset J, Carosella ED: Identification of HLA-G7 as a new splice variant of the HLA-G mRNA and expression of soluble HLA-G5, -G6, and -G7 transcripts in human transfected cells. Hum Immunol 2000; 61: 1138–1149.
- 18Rizzo R, Trentini A, Bortolotti D, Manfrinato MC, Rotola A, Castellazzi M, Melchiorri L, Di Luca D, Dallocchio F, Fainardi E, Bellini T: Matrix metalloproteinase-2 (MMP-2) generates soluble HLA-G1 by cell surface proteolytic shedding. Mol Cell Biochem 2013; 381: 243–255.
- 19Yie SM, Li LH, Li YM, Librach C: HLA-G protein concentrations in maternal serum and placental tissue are decreased in preeclampsia. Am J Obstet Gynecol 2004; 191: 525–529.
- 20Hackmon R, Koifman A, Hyodo H, Glickman H, Sheiner E, Geraghty DE: Reduced third-trimester levels of soluble human leukocyte antigen G protein in severe preeclampsia. Am J Obstet Gynecol 2007; 197: 255.e1,255.e5.
- 21Yie SM, Taylor RN, Librach C: Low plasma HLA-G protein concentrations in early gestation indicate the development of preeclampsia later in pregnancy. Am J Obstet Gynecol 2005; 193: 204–208.
- 22Rizzo R, Andersen AS, Lassen MR, Sørensen HC, Bergholt T, Larsen MH, Melchiorri L, Stignani M, Baricordi OR, Hviid TV: Soluble human leukocyte antigen-G isoforms in maternal plasma in early and late pregnancy. Am J Reprod Immunol 2009; 62: 320–338.
- 23Alegre E, Diaz-Lagares A, Lemaoult J, Lopez-Moratalla N, Carosella ED, Gonzalez A: Maternal antigen presenting cells are a source of plasmatic HLA-G during pregnancy: longitudinal study during pregnancy. Hum Immunol 2007; 68: 661–667.
- 24Oztekin O: New insights into the pathophysiology of gestational diabetes mellitus: possible role of human leukocyte antigen-G. Med Hypotheses 2007; 69: 526–530.
- 25Zhao YH, Wang DP, Zhang LL, Zhang F, Wang DM, Zhang WY: Genomic expression profiles of blood and placenta reveal significant immune-related pathways and categories in Chinese women with gestational diabetes mellitus. Diabet Med 2011; 28: 237–246.
- 26Farina A, Rapacchia G, Freni Sterrantino A, Pula G, Morano D, Rizzo N: Prospective evaluation of ultrasound and biochemical-based multivariable models for the prediction of late pre-eclampsia. Prenat Diagn 2011; 31: 1147–1152.
- 27Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, Hankins G, Berkowitz RL, Merkatz I, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Vidaver J, D'Alton ME: First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER trial). Am J Obstet Gynecol 2004; 191: 1446–1451.
- 28Montanari L, Alfei A, Albonico G, Moratti R, Arossa A, Beneventi F, Spinillo A: The impact of first-trimester serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A on the diagnosis of fetal growth restriction and small for gestational age infant. Fetal Diagn Ther 2009; 25: 130–135.
- 29Smith GC, Stenhouse EJ, Crossley JA, Aitken DA, Cameron AD, Connor JM: Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. J Clin Endocrinol Metab 2002; 87: 1762–1767.
- 30Spencer K, Cowans NJ, Spencer CE, Achillea N: A re-evaluation of the influence of maternal insulin-dependent diabetes on fetal nuchal translucency thickness and first-trimester maternal serum biochemical markers of aneuploidy. Prenat Diagn 2010; 30: 937–940.
- 31Savvidou MD, Syngelaki A, Muhaisen M, Emelyanenko E, Nicolaides KH: First trimester maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A in pregnancies complicated by diabetes mellitus. BJOG 2012; 119: 410–416.
- 32Lovati E, Beneventi F, Simonetta M, Laneri M, Quarleri L, Scudeller L, Albonico G, Locatelli E, Cavagnoli C, Tinelli C, Spinillo A, Corazza GR: Gestational diabetes mellitus: including serum pregnancy-associated plasma protein-A testing in the clinical management of primiparous women? A case–control study. Diabetes Res Clin Pract 2013; 100: 340–347.
- 33Atis A, Aydin Y, Basol E, Kaleli S, Turgay F, Goker N: PAPP-A levels of late pregnancy in preeclampsia and HELLP syndrome. Arch Gynecol Obstet 2012; 285: 45–49.
- 34Atis A, Tandogan T, Aydin Y, Sen C, Turgay F, Eren N, Goker N: Late pregnancy associated plasma protein A levels decrease in preterm labor. J Matern Fetal Neonatal Med 2011; 24: 923–927.
- 35Bowen JM, Chamley L, Keelan JA, Mitchell MD: Cytokines of the placenta and extra-placental membranes: roles and regulation during human pregnancy and parturition. Placenta 2002; 23: 257–273.
- 36Tutdibi E, Hunecke A, Lindner U, Monz D, Gortner L: Levels of cytokines in umbilical cord blood in relation to spontaneous term labor. J Perinat Med 2012; 40: 527–532.
- 37Hunt JS, Jadhav L, Chu W, Geraghty DE, Ober C: Soluble HLA-G circulates in maternal blood during pregnancy. Am J Obstet Gynecol 2000; 183: 682–688.
- 38Hunt JS, Langat DL: HLA-G: a human pregnancy-related immunomodulator. Curr Opin Pharmacol 2009; 9: 462–469.
- 39Goldman-Wohl DS, Ariel I, Greenfield C, Hochner-Celnikier D, Cross J, Fisher S, Yagel S: Lack of human leukocyte antigen-G expression in extravillous trophoblasts is associated with pre-eclampsia. Mol Hum Reprod 2000; 6: 88–95.
- 40Hviid TV: HLA-G in human reproduction: aspects of genetics, function and pregnancy complications. Hum Reprod Update 2006; 12: 209–232.
- 41Nardi FS, Slowik R, Wowk PF, da SJ, Gelmini GF, Michelon TF, Neumann J, Bicalho MG: Analysis of HLA-G polymorphisms in couples with implantation failure. Am J Reprod Immunol 2012; 68: 507–514.
- 42Zhou X, Zhang GY, Wang J, Lu SL, Cao J, Sun LZ: A novel bridge between oxidative stress and immunity: the interaction between hydrogen peroxide and human leukocyte antigen G in placental trophoblasts during preeclampsia. Am J Obstet Gynecol 2012; 206: 447.e7,447.16.
- 43Rudstein-Svetlicky N, Loewenthal R, Horejsi V, Gazit E: HLA-G levels in serum and plasma. Tissue Antigens 2006; 67: 111–116.
- 44Solini A, Muscelli E, Stignani M, Melchiorri L, Santini E, Rossi C, Astiarraga BD, Rizzo R, Baricordi OR: Soluble human leukocyte antigen-g expression and glucose tolerance in subjects with different degrees of adiposity. J Clin Endocrinol Metab 2010; 95: 3342–3346.
- 45Gueuvoghlanian-Silva BY, Torloni MR, Mattar R, de Oliveira LS, Scomparini FB, Nakamura MU, Daher S: Profile of inflammatory mediators in gestational diabetes mellitus: phenotype and genotype. Am J Reprod Immunol 2012; 67: 241–250.
- 46Unal ER, Cierny JT, Roedner C, Newman R, Goetzl L: Maternal inflammation in spontaneous term labor. Am J Obstet Gynecol 2011; 204: 223.e1,223.e5.
- 47Castillo-Castrejon M, Meraz-Cruz N, Gomez-Lopez N, Flores-Pliego A, Beltran-Montoya J, Viveros-Alcaraz M, Vadillo-Ortega F: Choriodecidual cells from term human pregnancies show distinctive functional properties related to the induction of labor. Am J Reprod Immunol 2014; 71: 86–93.