title: Increased placental expression and maternal serum levels of apoptosis-inducing TRAIL in recurrent miscarriage.
abstract: BACKGROUND
  Recurrent miscarriage (RM; ≥3 consecutive pregnancy losses) occurs in 1-3% of fertile couples. No biomarkers with high predictive value of threatening miscarriage have been identified. We aimed to profile whole-genome differential gene expression in RM placental tissue, and to determine the protein levels of identified loci in maternal sera in early pregnancy.
  
  
  METHODS
  GeneChips (Affymetrix(®)) were used for discovery and Taqman RT-qPCR assays for replication of mRNA expression in placentas from RM cases (n = 13) compared to uncomplicated pregnancies matched for gestational age (n = 23). Concentrations of soluble TRAIL (sTRAIL) and calprotectin in maternal serum in normal first trimester (n = 35) and failed pregnancies (early miscarriage, n = 18, late miscarriage, n = 4; tubal pregnancy, n = 11) were determined using ELISA.
  
  
  RESULTS
  In RM placentas 30 differentially expressed (with nominal P-value < 0.05) transcripts were identified. Significantly increased placental mRNA expression of TNF-related apoptosis-inducing ligand (TRAIL; P = 1.4 × 10(-3); fold-change 1.68) and S100A8 (P = 7.9 × 10(-4); fold-change 2.56) encoding for inflammatory marker calprotectin (S100A8/A9) was confirmed by RT-qPCR. When compared to normal first trimester pregnancy (sTRAIL 16.1 ± 1.6 pg/ml), significantly higher maternal serum concentration of sTRAIL was detected at the RM event (33.6 ± 4.3 pg/ml, P = 0.00027), and in pregnant women, who developed an unpredicted miscarriage 2-50 days after prospective serum sampling (28.5 ± 4.4 pg/ml, P = 0.039). Women with tubal pregnancy also exhibited elevated sTRAIL (30.5 ± 3.9 pg/ml, P = 0.035). Maternal serum levels of calprotectin were neither diagnostic nor prognostic to early pregnancy failures (P > 0.05).
  
  
  CONCLUSIONS
  The study indicated of sTRAIL as a potential predictive biomarker in maternal serum for early pregnancy complications.
authors.affiliation: Human Molecular Genetics Group, Institute of Molecular and Cell Biology, University of Tartu, Riia St. 23, Tartu 51010, Estonia.
authors.forename: K
authors.initials: K
authors.lastname: Rull
authors.forename: K
authors.initials: K
authors.lastname: Tomberg
authors.forename: S
authors.initials: S
authors.lastname: Kõks
authors.forename: J
authors.initials: J
authors.lastname: Männik
authors.forename: M
authors.initials: M
authors.lastname: Möls
authors.forename: M
authors.initials: M
authors.lastname: Sirotkina
authors.forename: S
authors.initials: S
authors.lastname: Värv
authors.forename: M
authors.initials: M
authors.lastname: Laan
mesh_terms: D000026:Abortion, Habitual / Q000097:blood* / Q000235:genetics*; D000328:Adult; D015415:Biomarkers / Q000097:blood; D040501:Calgranulin A / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D039841:Leukocyte L1 Antigen Complex / Q000097:blood; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000097:blood / Q000235:genetics; D011274:Pregnancy, Tubal / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000097:blood* / Q000235:genetics*
chemical_list: D015415:Biomarkers; D040501:Calgranulin A; D039841:Leukocyte L1 Antigen Complex; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human