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Preterm birth in Caucasians is associated with coagulation and inflammation pathway gene variants.

Velez DR, Fortunato SJ, Thorsen P, Lombardi SJ, Williams SM, Menon R - PLoS ONE (2008)

Bottom Line: In this pathway 3 of 6 genes examined had SNPs significantly associated with PTB.The single strongest effect was observed in tPA marker rs879293 with a significant allelic (p = 2.30x10(-3)) and genotypic association (p = 2.0x10(-6)) with PTB.These results support a role for genes in both the coagulation and inflammation pathways, and potentially different maternal and fetal genetic risks for PTB.

View Article: PubMed Central - PubMed

Affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.

ABSTRACT
Spontaneous preterm birth (<37 weeks gestation-PTB) occurs in approximately 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 = 2.30x10(-3)) and genotypic association (p = 2.0x10(-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 = 6.00x10(-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 = 3.34x10(-4)). The OR for the IL-10RA genotypic additive model was 1.92 [CI 1.15-3.19] (p = 2.00x10(-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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Associated genes in the complement and coagulation pathway subset.This branch of the complement and coagulation cascade had a cluster of three genes with significant results (α<0.05) at either the allele or genotype level (labeled in red). In addition to these genes we also genotyped markers in PAI1 from this branch and two genes from other branches of the complement and coagulation cascade (Soluble mannose-binding lectin 2 (MBL2), factor II (FII)); however, no markers in these genes were significant.
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pone-0003283-g002: Associated genes in the complement and coagulation pathway subset.This branch of the complement and coagulation cascade had a cluster of three genes with significant results (α<0.05) at either the allele or genotype level (labeled in red). In addition to these genes we also genotyped markers in PAI1 from this branch and two genes from other branches of the complement and coagulation cascade (Soluble mannose-binding lectin 2 (MBL2), factor II (FII)); however, no markers in these genes were significant.

Mentions: To further understand the significance of these variants in the pathophysiology of preterm birth a preliminary analysis was performed to putatively identify the potentially most important pathways. The complement and coagulation pathway had a significant excess of associations for both the allele and genotype tests in maternal data. The cytokine-cytokine receptor pathway was significant for both allele and genotype tests for fetal data. Upon examining the complement and coagulation pathway in more detail it was found that in the fibrinolytic branch of the pathway, three of four genes genotyped in that branch had markers that were significantly associated (Figure 2). These genes were factor VII (FVII), FV, and tPA. Two other genes upstream and downstream of this branch did not associate (soluble mannose-binding lectin (protein C) 2 (MBL2) and factor II [FII]). The only result to stand up to a Bonferroni correction was tPA, from the complement and coagulation cascade. A preliminary multi-locus analysis using multifactor dimensionality reduction (MDR) analysis revealed an interesting association between FV (rs2187952) and FVII (rs3211719) within the complement and coagulation cascade that suggests that there may be both an interaction among genes within the pathway and heterogeneity among these genes (Figure 1).


Preterm birth in Caucasians is associated with coagulation and inflammation pathway gene variants.

Velez DR, Fortunato SJ, Thorsen P, Lombardi SJ, Williams SM, Menon R - PLoS ONE (2008)

Associated genes in the complement and coagulation pathway subset.This branch of the complement and coagulation cascade had a cluster of three genes with significant results (α<0.05) at either the allele or genotype level (labeled in red). In addition to these genes we also genotyped markers in PAI1 from this branch and two genes from other branches of the complement and coagulation cascade (Soluble mannose-binding lectin 2 (MBL2), factor II (FII)); however, no markers in these genes were significant.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553267&req=5

pone-0003283-g002: Associated genes in the complement and coagulation pathway subset.This branch of the complement and coagulation cascade had a cluster of three genes with significant results (α<0.05) at either the allele or genotype level (labeled in red). In addition to these genes we also genotyped markers in PAI1 from this branch and two genes from other branches of the complement and coagulation cascade (Soluble mannose-binding lectin 2 (MBL2), factor II (FII)); however, no markers in these genes were significant.
Mentions: To further understand the significance of these variants in the pathophysiology of preterm birth a preliminary analysis was performed to putatively identify the potentially most important pathways. The complement and coagulation pathway had a significant excess of associations for both the allele and genotype tests in maternal data. The cytokine-cytokine receptor pathway was significant for both allele and genotype tests for fetal data. Upon examining the complement and coagulation pathway in more detail it was found that in the fibrinolytic branch of the pathway, three of four genes genotyped in that branch had markers that were significantly associated (Figure 2). These genes were factor VII (FVII), FV, and tPA. Two other genes upstream and downstream of this branch did not associate (soluble mannose-binding lectin (protein C) 2 (MBL2) and factor II [FII]). The only result to stand up to a Bonferroni correction was tPA, from the complement and coagulation cascade. A preliminary multi-locus analysis using multifactor dimensionality reduction (MDR) analysis revealed an interesting association between FV (rs2187952) and FVII (rs3211719) within the complement and coagulation cascade that suggests that there may be both an interaction among genes within the pathway and heterogeneity among these genes (Figure 1).

Bottom Line: In this pathway 3 of 6 genes examined had SNPs significantly associated with PTB.The single strongest effect was observed in tPA marker rs879293 with a significant allelic (p = 2.30x10(-3)) and genotypic association (p = 2.0x10(-6)) with PTB.These results support a role for genes in both the coagulation and inflammation pathways, and potentially different maternal and fetal genetic risks for PTB.

View Article: PubMed Central - PubMed

Affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.

ABSTRACT
Spontaneous preterm birth (<37 weeks gestation-PTB) occurs in approximately 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 = 2.30x10(-3)) and genotypic association (p = 2.0x10(-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 = 6.00x10(-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 = 3.34x10(-4)). The OR for the IL-10RA genotypic additive model was 1.92 [CI 1.15-3.19] (p = 2.00x10(-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.

Show MeSH
Related in: MedlinePlus