Polymorphisms in maternal and fetal genes encoding for proteins involved in extracellular matrix metabolism alter the risk for small-for-gestational-age.
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.
Edwards
Digna R Velez
DR
Department of Obstetrics and Gynecology, Vanderbilt Epidemiology Center, Institute of Medicine and Public Health, Vanderbilt University, Nashville, Tennessee, USA.
Romero
Roberto
R
Kusanovic
Juan Pedro
JP
Hassan
Sonia S
SS
Mazaki-Tovi
Shali
S
Vaisbuch
Edi
E
Kim
Chong Jai
CJ
Erez
Offer
O
Chaiworapongsa
Tinnakorn
T
Pearce
Brad D
BD
Bartlett
Jacquelaine
J
Friel
Lara A
LA
Salisbury
Benjamin A
BA
Anant
Madan Kumar
MK
Vovis
Gerald F
GF
Lee
Min Seob
MS
Gomez
Ricardo
R
Behnke
Ernesto
E
Oyarzun
Enrique
E
Tromp
Gerard
G
Menon
Ramkumar
R
Williams
Scott M
SM
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
D011506:Proteins