TY - JOUR
T1 - Polymorphisms in maternal and fetal genes encoding for proteins involved in extracellular matrix metabolism alter the risk for small-for-gestational-age
AU - Edwards, Digna R.Velez
AU - Romero, Roberto
AU - Kusanovic, Juan Pedro
AU - Hassan, Sonia S.
AU - Mazaki-Tovi, Shali
AU - Vaisbuch, Edi
AU - Kim, Chong Jai
AU - Erez, Offer
AU - Chaiworapongsa, Tinnakorn
AU - Pearce, Brad D.
AU - Bartlett, Jacquelaine
AU - Friel, Lara A.
AU - Salisbury, Benjamin A.
AU - Anant, Madan Kumar
AU - Vovis, Gerald F.
AU - Lee, Min Seob
AU - Gomez, Ricardo
AU - Behnke, Ernesto
AU - Oyarzun, Enrique
AU - Tromp, Gerard
AU - Menon, Ramkumar
AU - Williams, Scott M.
N1 - Funding Information:
This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS.
PY - 2011/2
Y1 - 2011/2
N2 - Objective. To examine the association between maternal and fetal genetic variants and small-for-gestational-age (SGA). Methods. A casecontrol 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.
AB - Objective. To examine the association between maternal and fetal genetic variants and small-for-gestational-age (SGA). Methods. A casecontrol 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.
KW - DNA variants
KW - SNP
KW - complex disease
KW - extracellular matrix
KW - genetic association study
KW - genetic epidemiology
KW - genomics
KW - genotype
KW - haplotype
KW - high dimensional biology
KW - intrauterine growth restriction
UR - http://www.scopus.com/inward/record.url?scp=78651423018&partnerID=8YFLogxK
U2 - 10.3109/14767058.2010.497572
DO - 10.3109/14767058.2010.497572
M3 - Article
C2 - 20617897
AN - SCOPUS:78651423018
SN - 1476-7058
VL - 24
SP - 362
EP - 380
JO - Journal of Maternal-Fetal and Neonatal Medicine
JF - Journal of Maternal-Fetal and Neonatal Medicine
IS - 2
ER -