Multidimensional System Biology: Genetic Markers and Proteomic Biomarkers of Adverse Pregnancy Outcome in Preterm Birth

ABSTRACT

Premature birth before 37 weeks of gestation is a significant public health problem. Each year, 4.5 million premature infants are born worldwide. Despite extensive research and a variety of interventions, the rate of preterm birth has steadily increased over the past 20 years and reached a high of 12.8% in 2006. The etiology of most preterm births remains elusive and is likely multifactorial, with many pathophysiological pathways involved, such as excessive stretching, oxidative stress, decidual hemorrhage, and infection. Genomics and proteomics have emerged to provide a better comprehension of the pathophysiological conditions leading to preterm birth, thereby providing a perspective for improving neonatal outcome.

KEYWORDS

Preterm birth - genomics - proteomics

REFERENCES

• 1 Hamilton B E, Martin J A, Ventura S J. Births: final data for 2006.  National Vital Statistics Reports. 2007;  56 1-18
• 2 Clements K M, Barfield W D, Ayadi M F et al.. Preterm birth-associated cost of early intervention services: an analysis by gestational age.  Pediatrics. 2007;  119 e866-e874
• 3 Flores-Santos R, Hernandez-Cabrera M A, Henandez-Herrera R J, Sepulveda-Canamar F. Screening for retinopathy of prematurity: results of a 7-year study of underweight newborns.  Arch Med Res. 2007;  38 440-443
• 4 Patra K, Wilson-Costello D, Taylor H G et al.. Grades I-II intraventricular hemorrhage in extremely low birth weight infants: effects on neurodevelopment.  J Pediatr. 2006;  149 169-173
• 5 Hintz S R, Kendrick D E, Vohr B R. National Institute of Child Health and Human Development Neonatal Research Network. Changes in neurodevelopmental outcomes at 18 to 22 months' corrected age among infants of less than 25 weeks' gestational age born in 1993-1999.  Pediatrics. 2005;  115 1645-1651
• 6 Vincer M J, Allen A C, Joseph K S et al.. Increasing prevalence of cerebral palsy among very preterm infants: a population-based study.  Pediatrics. 2006;  118 e1621-e1626
• 7 Bhandari A, Bhandari V. Pathogenesis, pathology and pathophysiology of pulmonary sequelae of bronchopulmonary dysplasia in premature infants.  Front Biosci. 2003;  8 e370-e380
• 8 Grimes D A, Nanda K. Magnesium sulfate tocolysis: time to quit.  Obstet Gynecol. 2006;  108 986-989
• 9 Thornton J G. Maintenance tocolysis.  BJOG. 2005;  112 118-121
• 10 Hollier L M. Preventing preterm birth: what works, what doesn't.  Obstet Gynecol Surv. 2005;  60 124-131
• 11 Coomarasamy A, Knox E M, Gee H et al.. Effectiveness of nifedipine versus atosiban for tocolysis in preterm labour: a meta-analysis with an indirect comparison of randomised trials.  BJOG. 2003;  110 1045-1049
• 12 King J, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for treating preterm labour.  Cochrane Database Syst Rev. 2005;  2 CD001992
• 13 Combs C A, McCune M, Clark R et al.. Aggressive tocolysis does not prolong pregnancy or reduce neonatal morbidity after preterm premature rupture of the membranes.  Am J Obstet Gynecol. 2004;  190 1723-1728
• 14 Lockwood C J. Testing for risk of preterm delivery.  Clin Lab Med. 2003;  23 345-360
• 15 Watson J D, Crick F H. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid.  Nature. 1953;  25 737-738
• 16 Venter J C, Adams M D, Myers E W et al.. The sequence of the human genome.  Science. 2001;  291 1304-1351
• 17 US Department of Health and Human Services .“Innovation or Stagnation?-Challenge and Opportunity on the Critical Path to New Medical Products”. March 2004
• 18 Lander E S, Schork N J. Genetic dissection of complex traits.  Science. 1994;  265 2037-2048
• 19 Zhu T, Salmeron J. High-definition genome profiling for genetic marker discovery.  Trends Plant Sci. 2007;  12 196-202
• 20 Hao K, Wang X, Niu T et al.. A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods.  Hum Mol Genet. 2004;  13 683-691
• 21 Hillebrandt S, Matern S, Lammert F. Mouse models for genetic dissection of polygenic gastrointestinal diseases.  Eur J Clin Invest. 2003;  33 155-160
• 22 Nesin M. Genetic basis of preterm birth.  Front Biosci. 2007;  12 115-124
• 23 Lee S J, Steer P J, Filippi V. Seasonal patterns and preterm birth: a systematic review of the literature and an analysis in a London-based cohort.  BJOG. 2006;  113 1280-1288
• 24 Gilbreath S, Kass P H. Adverse birth outcomes associated with open dumpsites in Alaska native villages.  Am J Epidemiol. 2006;  164 518-528
• 25 Macones G A, Parry S, Elkousy M et al.. A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth.  Am J Obstet Gynecol. 2004;  190 1504-1508
• 26 Crider K S, Whitehead N, Buus R M. Genetic variation associated with preterm birth: a HuGE review.  Genet Med. 2005;  7 593-604
• 27 Selling K E, Carstensen J, Finnstrom O et al.. Intergenerational effects of preterm birth and reduced intrauterine growth: a population-based study of Swedish mother-offspring pairs.  BJOG. 2006;  113 430-440
• 28 Melve K K, Skjaerven R, Gjessing H K et al.. Recurrence of gestational age in sibships: implications for perinatal mortality.  Am J Epidemiol. 1999;  150 756-762
• 29 Winkvist A, Mogren I, Hogberg U. Familial patterns in birth characteristics: impact on individual and population risks.  Int J Epidemiol. 1998;  27 248-254
• 30 Porter T F, Fraser A M, Hunter C Y et al.. The risk of preterm birth across generations.  Obstet Gynecol. 1997;  90 63-67
• 31 Ward K, Argyle V, Meade M et al.. The heritability of preterm delivery.  Obstet Gynecol. 2005;  106 1235-1239
• 32 Treloar S A, Macones G A, Mitchell L E et al.. Genetic influences on premature parturition in an Australian twin sample.  Twin Res. 2000;  3 80-82
• 33 Aguan K, Carvajal J A, Thompson L P et al.. Application of a functional genomics approach to identify differentially expressed genes in human myometrium during pregnancy and labour.  Mol Hum Reprod. 2000;  6 1141-1145
• 34 Havelock J C, Keller P, Muleba N et al.. Human myometrial gene expression before and during parturition.  Biol Reprod. 2005;  72 707-719
• 35 Chan E C, Fraser S, Yin S. Human myometrial genes are differentially expressed in labor: a suppression subtractive hybridization study.  J Clin Endocrinol Metab. 2002;  87 2435-2441
• 36 Bukowski R, Hankins G D, Saade G R et al.. Labor-associated gene expression in the human uterine fundus, lower segment, and cervix.  PLoS Med. 2006;  3 e169
• 37 Mason C W, Buhimschi C S, Swaan P W et al.. Molecular genetic regulation of human myometrial activation and quiescence.  , Abstract #238 J Soc Gynecol Invest. 2006;  13 140A
• 38 Mason C W, Buhimschi C S, Swaan P W et al.. Genomic 'prime time' players in preterm labor and term labor.  , Abstract #239 J Soc Gynecol Invest. 2006;  13 141A
• 39 Buhimschi C S, Mason C W, Swaan P W et al.. Evidence that innate immunity is activated in myometrium from women in term and preterm labor.  , Abstract #221 J Soc Gynecol Invest. 2006;  13 135A
• 40 Azuaje F, Al-Shahrour F, Dopazo J. Ontology-driven approaches to analyzing data in functional genomics.  Methods Mol Biol. 2006;  316 67-86
• 41 Scharpf R B, Ting J C, Pevsner J, Ruczinski I. SNP chip: R classes and methods for SNP array data.  Bioinformatics. 2007;  23 627-628
• 42 Meirhaeghe A, Boreham C A, Murray L J. A possible role for the PPARG Pro12Ala polymorphism in preterm birth.  Diabetes. 2007;  56 494-498
• 43 Murtha A P, Nieves A, Hauser E R et al.. Association of maternal IL-1 receptor antagonist intron 2 gene polymorphism and preterm birth.  Am J Obstet Gynecol. 2006;  195 1249-1253
• 44 Menon R, Merialdi M, Betran A P. Analysis of association between maternal tumor necrosis factor-alpha promoter polymorphism (-308), tumor necrosis factor concentration, and preterm birth.  Am J Obstet Gynecol. 2006;  195 1240-1248
• 45 Wang H, Parry S, Macones G et al.. A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans.  Proc Natl Acad Sci U S A. 2006;  103 13463-13467
• 46 Bodamer O A, Mitterer G, Maurer W et al.. Evidence for an association between mannose binding lectin 2 (MBL2) gene polymorphisms and pre-term birth.  Genet Med. 2006;  8 518-524
• 47 Menon R, Velez D R, Simhan H et al.. Multilocus interactions at maternal tumor necrosis factor-alpha, tumor necrosis factor receptors, interleukin-6 and interleukin-6 receptor genes predict spontaneous preterm labor in European-American women.  Am J Obstet Gynecol. 2006;  194 1616-1624
• 48 Lawlor D A, Gaunt T R, Hinks L J et al.. The association of the PON1 Q192R polymorphism with complications and outcomes of pregnancy: findings from the British Women's Heart and Health cohort study.  Paediatr Perinat Epidemiol. 2006;  20 244-250
• 49 Chen D, Hu Y, Chen C et al.. Polymorphisms of the paraoxonase gene and risk of preterm delivery.  Epidemiology. 2004;  15 466-470
• 50 Kalish R B, Vardhana S, Normand N J et al.. Association of a maternal CD14 -159 gene polymorphism with preterm premature rupture of membranes and spontaneous preterm birth in multi-fetal pregnancies.  J Reprod Immunol. 2006;  70 109-117
• 51 Hartel C, von Otte S, Koch J et al.. Polymorphisms of haemostasis genes as risk factors for preterm delivery.  Thromb Haemost. 2005;  94 88-92
• 52 Engel S A, Erichsen H C, Savitz D A et al.. Risk of spontaneous preterm birth is associated with common proinflammatory cytokine polymorphisms.  Epidemiology. 2005;  16 469-477
• 53 Johnson W G, Scholl T O, Spychala J R et al.. Common dihydrofolate reductase 19-base pair deletion allele: a novel risk factor for preterm delivery.  Am J Clin Nutr. 2005;  81 664-668
• 54 Engel S A, Erichsen H C, Savitz D A et al.. Risk of spontaneous preterm birth is associated with common proinflammatory cytokine polymorphisms.  Epidemiology. 2005;  16 469-477
• 55 Kalish R B, Nguyen D P, Vardhana S et al.. A single nucleotide A> G polymorphism at position -670 in the Fas gene promoter: relationship to preterm premature rupture of fetal membranes in multifetal pregnancies.  Am J Obstet Gynecol. 2005;  192 208-212
• 56 Annells M F, Hart P H, Mullighan C G et al.. Interleukins-1, -4, -6, -10, tumor necrosis factor, transforming growth factor-beta, FAS, and mannose-binding protein C gene polymorphisms in Australian women: risk of preterm birth.  Am J Obstet Gynecol. 2004;  191 2056-2067
• 57 Hartel C H, Finas D, Ahrens P et al.. Genetic factors in Neonatology Study Group. Polymorphisms of genes involved in innate immunity: association with preterm delivery.  Mol Hum Reprod. 2004;  10 911-915
• 58 Resch B, Gallistl S, Kutschera J et al.. Thrombophilic polymorphisms-factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations-and preterm birth.  Wien Klin Wochenschr. 2004;  116 622-626
• 59 Amory J H, Adams K M, Lin M T et al.. Adverse outcomes after preterm labor are associated with tumor necrosis factor-alpha polymorphism -863, but not -308, in mother-infant pairs.  Am J Obstet Gynecol. 2004;  191 1362-1367
• 60 Genc M R, Onderdonk A B, Vardhana S et al.. MAP Study Group. Polymorphism in intron 2 of the interleukin-1 receptor antagonist gene, local midtrimester cytokine response to vaginal flora, and subsequent preterm birth.  Am J Obstet Gynecol. 2004;  191 1324-1330
• 61 Nguyen D P, Genc M, Vardhana S et al.. Ethnic differences of polymorphisms in cytokine and innate immune system genes in pregnant women.  Obstet Gynecol. 2004;  104 293-300
• 62 Valdez L L, Quintero A, Garcia E et al.. Thrombophilic polymorphisms in preterm delivery.  Blood Cells Mol Dis. 2004;  33 51-56
• 63 Kalish R B, Vardhana S, Gupta M et al.. Interleukin-4 and -10 gene polymorphisms and spontaneous preterm birth in multifetal gestations.  Am J Obstet Gynecol. 2004;  190 702-706
• 64 Moore S, Ide M, Randhawa M et al.. An investigation into the association among preterm birth, cytokine gene polymorphisms and periodontal disease.  BJOG. 2004;  111 125-132
• 65 Wang H, Parry S, Macones G et al.. Functionally significant SNP MMP8 promoter haplotypes and preterm premature rupture of membranes (PPROM).  Hum Mol Genet. 2004;  13 2659-2669
• 66 Ferrand P E, Parry S, Sammel M et al.. A polymorphism in the matrix metalloproteinase-9 promoter is associated with increased risk of preterm premature rupture of membranes in African Americans.  Mol Hum Reprod. 2002;  8 494-501
• 67 Witkin S S, Vardhana S, Yih M et al.. Polymorphism in intron 2 of the fetal interleukin-1 receptor antagonist genotype influences midtrimester amniotic fluid concentrations of interleukin-1beta and interleukin-1 receptor antagonist and pregnancy outcome.  Am J Obstet Gynecol. 2003;  189 1413-1417
• 68 Simhan H N, Krohn M A, Roberts J M et al.. Interleukin-6 promoter -174 polymorphism and spontaneous preterm birth.  Am J Obstet Gynecol. 2003;  189 915-918
• 69 Lorenz E, Hallman M, Marttila R et al.. Association between the Asp299Gly polymorphisms in the Toll-like receptor 4 and premature births in the Finnish population.  Pediatr Res. 2002;  52 373-376
• 70 Aidoo M, McElroy P D, Kolczak M S et al.. Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX.  Genet Epidemiol. 2001;  21 201-211
• 71 Roberts A K, Monzon-Bordonaba F, Van Deerlin P G et al.. Association of polymorphism within the promoter of the tumor necrosis factor alpha gene with increased risk of preterm premature rupture of the fetal membranes.  Am J Obstet Gynecol. 1999;  180 1297-1302
• 72 Orsi N M, Gopichandran N, Simpson N A. Genetics of preterm labour.  Best Pract Res Clin Obstet Gynaecol. 2007;  21(5) 757-772
• 73 Densem C G, Hutchinson I V, Yonan N et al.. Donor and recipient-transforming growth factor-beta 1 polymorphism and cardiac transplant-related coronary artery disease.  Transpl Immunol. 2004;  13 211-217
• 74 Sinsheimer J S, Palmer C G, Woodward J A. Detecting genotype combinations that increase risk for disease: maternal-fetal genotype incompatibility test.  Genet Epidemiol. 2003;  24 1-13
• 75 The International HapMap Consortium . The International HapMap Project.  Nature. 2003;  426 789-796
• 76 Lieber C D. Introduction to proteomics. In: Lieber CD Tools for the New Biology. Totowa, NJ; Humana Press 2002: 3-14
• 77 Tammen H, Peck A, Budde P et al.. Peptidomics analysis of human blood specimens for biomarker discovery.  Expert Rev Mol Diagn. 2007;  7 605-613
• 78 Buhimschi C S, Weiner C P, Buhimschi I A. Clinical proteomics: a novel diagnostic tool for the new biology of preterm labor: PartI Proteomics tools.  Obstet Gynecol Surv. 2006;  61 481-486
• 79 Bahtiyar M O, Copel J A, Mahoney M J et al.. Proteomics: a novel methodology to complement prenatal diagnosis of chromosomal abnormalities and inherited human diseases.  Am J Perinatol. 2007;  24 167-181
• 80 Lockwood C J. Pregnancy-associated changes in the hemostatic system.  Clin Obstet Gynecol. 2006;  49 836-843
• 81 Salafia C M, Lopez-Zeno J A, Sherer D M et al.. Histologic evidence of old intrauterine bleeding is more frequent in prematurity.  Am J Obstet Gynecol. 1995;  173 1065-1070
• 82 Lockwood C J, Krikun G, Rahman M et al.. The role of decidualization in regulating endometrial hemostasis during the menstrual cycle, gestation, and in pathological states.  Semin Thromb Hemost. 2007;  33 111-117
• 83 Weiner C P, Lee K Y, Buhimschi C S et al.. Proteomic biomarkers that predict the clinical success of rescue cerclage.  Am J Obstet Gynecol. 2005;  192 710-718
• 84 Buhimschi I A, Christner R, Buhimschi C S. Proteomic biomarker analysis of amniotic fluid for identification of intra-amniotic inflammation.  BJOG. 2005;  112 173-181
• 85 ACOG Committee on Practice Bulletins-Obstetrics . ACOG Practice Bulletin No. 80: Premature rupture of membranes. Clinical management guidelines for obstetrician-gynecologists.  Obstet Gynecol. 2007;  109 1007-1019
• 86 Locatelli A, Ghidini A, Paterlini G et al.. Gestational age at preterm premature rupture of membranes: a risk factor for neonatal white matter damage.  Am J Obstet Gynecol. 2005;  193 947-951
• 87 Buhimschi I A, Kramer W B, Buhimschi C S. Reduction-oxidation (redox) state regulation of matrix metalloproteinase activity in human fetal membranes.  Am J Obstet Gynecol. 2000;  182 458-464
• 88 Menon R, Fortunato S J. The role of matrix degrading enzymes and apoptosis in rupture of membranes.  J Soc Gynecol Investig. 2004;  11 427-437
• 89 Vuadens F, Benay C, Crettaz D et al.. Identification of biologic markers of the premature rupture of fetal membranes: proteomic approach.  Proteomics. 2003;  3 1521-1525
• 90 Thadikkaran L, Crettaz D, Siegenthaler M A et al.. The role of proteomics in the assessment of premature rupture of fetal membranes.  Clin Chim Acta. 2005;  360 27-36
• 91 Michel P E, Crettaz D, Morier P et al.. Proteome analysis of human plasma and amniotic fluid by Off-Gel isoelectric focusing followed by nano-LC-MS/MS.  Electrophoresis. 2006;  27 1169-1181
• 92 Davis N M, Ford G W, Anderson P J et al.. Developmental coordination disorder at 8 years of age in a regional cohort of extremely-low-birthweight or very preterm infants.  Dev Med Child Neurol. 2007;  49 325-330
• 93 Maalouf E F, Duggan P J, Rutherford M A et al.. Magnetic resonance imaging of the brain in a cohort of extremely preterm infants.  J Pediatr. 1999;  135 351-357
• 94 Green N S, Damus K, Simpson J L et al.. March of Dimes Scientific Advisory Committee on Prematurity. Research agenda for preterm birth: recommendations from the March of Dimes.  Am J Obstet Gynecol. 2005;  193 626-635
• 95 Gravett M G, Novy M J, Rosenfeld R G et al.. Diagnosis of intra-amniotic infection by proteomic profiling and identification of novel biomarkers.  JAMA. 2004;  292 462-469
• 96 Vuadens F, Benay C, Crettaz D et al.. Identification of biologic markers of the premature rupture of fetal membranes: proteomic approach.  Proteomics. 2003;  3 1521-1525
• 97 Michel P E, Crettaz D, Morier P et al.. Proteome analysis of human plasma and amniotic fluid by Off-Geltrade mark isoelectric focusing followed by nano-LC-MS/MS.  Electrophoresis. 2006;  27 1169-1181
• 98 Ruetschi U, Rosen A, Karlsson G et al.. Proteomic analysis using protein chips to detect biomarkers in cervical and amniotic fluid in women with intra-amniotic inflammation.  J Proteome Res. 2005;  4 2236-2242
• 99 Buhimschi C S, Pettker C M, Magloire L K et al.. Proteomic technology and delayed interval delivery in multiple pregnancies.  Int J Gynaecol Obstet. 2005;  90 48-50
• 100 Buhimschi C S, Weiner C P, Buhimschi I A. Proteomics: Part II The emerging role of proteomics over genomics in spontaneous preterm labor/birth.  Obstet Gynecol Surv. 2006;  61 543-553
• 101 Sampson J E, Theve R P, Blatman R N et al.. Fetal origin of amniotic fluid polymorphonuclear leukocytes.  Am J Obstet Gynecol. 1997;  176 77-81
• 102 Buhimschi C S, Bhandari V, Hamar B D et al.. Proteomic profiling of the amniotic fluid to detect inflammation, infection, and neonatal sepsis.  PLoS Med. 2007;  4 e18
• 103 Nien J K, Yoon B H, Espinoza J et al.. A rapid MMP-8 bedside test for the detection of intra-amniotic inflammation identifies patients at risk for imminent preterm delivery.  Am J Obstet Gynecol. 2006;  195 1025-1030
• 104 Bianchi D W. At-home fetal DNA gender testing: caveat emptor.  Obstet Gynecol. 2006;  107 216-218
• 105 Di Quinzio M K, Oliva K, Holdsworth S J et al.. Proteomic analysis and characterisation of human cervico-vaginal fluid proteins.  Aust N Z J Obstet Gynaecol. 2007;  47 9-15
• 106 Pereira L, Reddy A P, Jacob T et al.. Identification of novel protein biomarkers of preterm birth in human cervical-vaginal fluid.  J Proteome Res. 2007;  6 1269-1276
• 107 Buhimschi I A, Buhimschi C S, Weiner C P et al.. Proteomic but not enzyme-linked immunosorbent assay technology detects amniotic fluid monomeric calgranulins from their complexed calprotectin form.  Clin Diagn Lab Immunol. 2005;  12 837-844
• 108 Buhimschi I A, Buhimschi C S, Hamar B et al.. Proteomic analysis of the vaginal amniotic fluid in patients with preterm premature rupture of the membranes (PPROM).  , Abstract #287 Am J Obstet Gynecol. 2004;  191 S87
• 109 Buhimschi I A, Buhimschi C S, Weiner C P. Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation.  Am J Obstet Gynecol. 2003;  188 203-208
• 110 Beloosesky R, Gayle D A, Amidi F et al.. N-acetyl-cysteine suppresses amniotic fluid and placenta inflammatory cytokine responses to lipopolysaccharide in rats.  Am J Obstet Gynecol. 2006;  194 268-273