TY - JOUR
T1 - Preterm birth in Caucasians is associated with coagulation and inflammation pathway gene variants
AU - Velez, Digna R.
AU - Fortunato, Stephen J.
AU - Thorsen, Poul
AU - Lombardi, Salvatore J.
AU - Williams, Scott M.
AU - Menon, Ramkumar
PY - 2008/9/26
Y1 - 2008/9/26
N2 - Spontaneous preterm birth (<37 weeks gestation - PTB) occurs in ∼ 12% of pregnancies in the United States, and is the largest contributor to neonatal morbidity and mortality. PTB is a complex disease, potentially induced by several etiologic factors from multiple pathophysiologic pathways. To dissect the genetic risk factors of PTB a large-scale high-throughput candidate gene association study was performed examining 1536 SNP in 130 candidate genes from hypothesized PTB pathways. Maternal and fetal DNA from 370 US Caucasian birth-events (172 cases and 198 controls) was examined. Single locus, haplotype, and multi-locus association analyses were performed separately on maternal and fetal data. For maternal data the strongest associations were found in genes in the complement-coagulation pathway related to decidual hemorrhage in PTB. In this pathway 3 of 6 genes examined had SNPs significantly associated with PTB. These include factor V (FV) that was previously associated with PTB, factor VII (FVII), and tissue plasminogen activator (tPA). The single strongest effect was observed in tPA marker rs879293 with a significant allelic (p = 2.30 × 10-3) and genotypic association (p = 2.06 × 10-6) with PTB. The odds ratio (OR) for this SNP was 2.80 [CI 1.77-4.44] for a recessive model. Given that 6 of 8 markers in tPA were statistically significant, sliding window haplotype analyses were performed and revealed an associating 4 marker haplotype in tPA (p = 6.00 × 10-3). The single strongest effect in fetal DNA was observed in the inflammatory pathway at rs17121510 in the interleukin-10 receptor antagonist (IL-10RA) gene for allele (p = 0.01) and genotype (p = 3.34 × 10-4). The OR for the IL-10RA genotypic additive model was 1.92 [CI 1.15-3.19] (p = 2.00 × 10-3). Finally, exploratory multi-locus analyses in the complement and coagulation pathway were performed and revealed a potentially significant interaction between a marker in FV (rs2187952) and FVII (rs3211719) (p<0.001). These results support a role for genes in both the coagulation and inflammation pathways, and potentially different maternal and fetal genetic risks for PTB.
AB - Spontaneous preterm birth (<37 weeks gestation - PTB) occurs in ∼ 12% of pregnancies in the United States, and is the largest contributor to neonatal morbidity and mortality. PTB is a complex disease, potentially induced by several etiologic factors from multiple pathophysiologic pathways. To dissect the genetic risk factors of PTB a large-scale high-throughput candidate gene association study was performed examining 1536 SNP in 130 candidate genes from hypothesized PTB pathways. Maternal and fetal DNA from 370 US Caucasian birth-events (172 cases and 198 controls) was examined. Single locus, haplotype, and multi-locus association analyses were performed separately on maternal and fetal data. For maternal data the strongest associations were found in genes in the complement-coagulation pathway related to decidual hemorrhage in PTB. In this pathway 3 of 6 genes examined had SNPs significantly associated with PTB. These include factor V (FV) that was previously associated with PTB, factor VII (FVII), and tissue plasminogen activator (tPA). The single strongest effect was observed in tPA marker rs879293 with a significant allelic (p = 2.30 × 10-3) and genotypic association (p = 2.06 × 10-6) with PTB. The odds ratio (OR) for this SNP was 2.80 [CI 1.77-4.44] for a recessive model. Given that 6 of 8 markers in tPA were statistically significant, sliding window haplotype analyses were performed and revealed an associating 4 marker haplotype in tPA (p = 6.00 × 10-3). The single strongest effect in fetal DNA was observed in the inflammatory pathway at rs17121510 in the interleukin-10 receptor antagonist (IL-10RA) gene for allele (p = 0.01) and genotype (p = 3.34 × 10-4). The OR for the IL-10RA genotypic additive model was 1.92 [CI 1.15-3.19] (p = 2.00 × 10-3). Finally, exploratory multi-locus analyses in the complement and coagulation pathway were performed and revealed a potentially significant interaction between a marker in FV (rs2187952) and FVII (rs3211719) (p<0.001). These results support a role for genes in both the coagulation and inflammation pathways, and potentially different maternal and fetal genetic risks for PTB.
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U2 - 10.1371/journal.pone.0003283
DO - 10.1371/journal.pone.0003283
M3 - Article
C2 - 18818748
AN - SCOPUS:53749084482
SN - 1932-6203
VL - 3
JO - PloS one
JF - PloS one
IS - 9
M1 - e3283
ER -