title: Polymorphisms in maternal and fetal genes encoding for proteins involved in extracellular matrix metabolism alter the risk for small-for-gestational-age.
abstract: OBJECTIVE
  To examine the association between maternal and fetal genetic variants and small-for-gestational-age (SGA).
  
  
  METHODS
  A case-control study was conducted in patients with SGA neonates (530 maternal and 436 fetal) and controls (599 maternal and 628 fetal); 190 candidate genes and 775 SNPs were studied. Single-locus, multi-locus and haplotype association analyses were performed on maternal and fetal data with logistic regression, multifactor dimensionality reduction (MDR) analysis, and haplotype-based association with 2 and 3 marker sliding windows, respectively. Ingenuity pathway analysis (IPA) software was used to assess pathways that associate with SGA.
  
  
  RESULTS
  The most significant single-locus association in maternal data was with a SNP in tissue inhibitor of metalloproteinase 2 (TIMP2) (rs2277698 OR = 1.71, 95% CI [1.26-2.32], p = 0.0006) while in the fetus it was with a SNP in fibronectin 1 isoform 3 preproprotein (FN1) (rs3796123, OR = 1.46, 95% CI [1.20-1.78], p = 0.0001). Both SNPs were adjusted for potential confounders (maternal body mass index and fetal sex). Haplotype analyses resulted in associations in α 1 type I collagen preproprotein (COL1A1, rs1007086-rs2141279-rs17639446, global p = 0.006) in mothers and FN1 (rs2304573-rs1250204-rs1250215, global p = 0.045) in fetuses. Multi-locus analyses with MDR identified a two SNP model with maternal variants collagen type V α 2 (COL5A2) and plasminogen activator urokinase (PLAU) predicting SGA outcome correctly 59% of the time (p = 0.035).
  
  
  CONCLUSIONS
  Genetic variants in extracellular matrix-related genes showed significant single-locus association with SGA. These data are consistent with other studies that have observed elevated circulating fibronectin concentrations in association with increased risk of SGA. The present study supports the hypothesis that DNA variants can partially explain the risk of SGA in a cohort of Hispanic women.
authors.affiliation: Department of Obstetrics and Gynecology, Vanderbilt Epidemiology Center, Institute of Medicine and Public Health, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Digna R Velez
authors.initials: DR
authors.lastname: Edwards
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Kusanovic
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
authors.forename: Shali
authors.initials: S
authors.lastname: Mazaki-Tovi
authors.forename: Edi
authors.initials: E
authors.lastname: Vaisbuch
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
authors.forename: Offer
authors.initials: O
authors.lastname: Erez
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.forename: Brad D
authors.initials: BD
authors.lastname: Pearce
authors.forename: Jacquelaine
authors.initials: J
authors.lastname: Bartlett
authors.forename: Lara A
authors.initials: LA
authors.lastname: Friel
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Salisbury
authors.forename: Madan Kumar
authors.initials: MK
authors.lastname: Anant
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Vovis
authors.forename: Min Seob
authors.initials: MS
authors.lastname: Lee
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gomez
authors.forename: Ernesto
authors.initials: E
authors.lastname: Behnke
authors.forename: Enrique
authors.initials: E
authors.lastname: Oyarzun
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D005317:Fetal Growth Retardation / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age / Q000502:physiology; D008297:Male; D033261:Maternal-Fetal Relations / Q000502:physiology; D053858:Metabolic Networks and Pathways / Q000235:genetics; D009035:Mothers; D058011:Multifactor Dimensionality Reduction; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D012307:Risk Factors; D055815:Young Adult
chemical_list: D011506:Proteins