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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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MDR complement and coagulation two locus model between FV and FVII.a. Testing accuracy and cross validation consistency for the best one to three locus models. b. Best multilocus model in the complement and coagulation pathway - Each multifactor cell is labeled as “high risk” or “low risk”. For each multifactor combination, hypothetical distributions of cases (left bar in cell) and controls (right bar in cell) are shown. Each cell represents a multilocus genotype; the genotype is labeled on the figure. The testing average balanced accuracy is 61.58% (p-value<1.00×10−3) with a cross-validation consistency of 10/10. Logistic regression analyses showed that the interaction for the effects of these two markers was statistically significant (p = 0.009) and the likelihood ratio test p value for including the interaction in the logistic regression model was 0.0072.
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pone-0003283-g001: MDR complement and coagulation two locus model between FV and FVII.a. Testing accuracy and cross validation consistency for the best one to three locus models. b. Best multilocus model in the complement and coagulation pathway - Each multifactor cell is labeled as “high risk” or “low risk”. For each multifactor combination, hypothetical distributions of cases (left bar in cell) and controls (right bar in cell) are shown. Each cell represents a multilocus genotype; the genotype is labeled on the figure. The testing average balanced accuracy is 61.58% (p-value<1.00×10−3) with a cross-validation consistency of 10/10. Logistic regression analyses showed that the interaction for the effects of these two markers was statistically significant (p = 0.009) and the likelihood ratio test p value for including the interaction in the logistic regression model was 0.0072.

Mentions: Multilocus analyses on pathways with an excess of significant associations for either allele or genotype tests (identified by Z tests analyses) revealed a statistically significant two locus model in the complement and coagulation pathway in maternal data after excluding the single most significant tPA marker (rs879293) (Figure 1). This model included markers from Factor V and Factor VII with a balanced testing accuracy of 61.58% and a cross validation consistency of 10.


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)

MDR complement and coagulation two locus model between FV and FVII.a. Testing accuracy and cross validation consistency for the best one to three locus models. b. Best multilocus model in the complement and coagulation pathway - Each multifactor cell is labeled as “high risk” or “low risk”. For each multifactor combination, hypothetical distributions of cases (left bar in cell) and controls (right bar in cell) are shown. Each cell represents a multilocus genotype; the genotype is labeled on the figure. The testing average balanced accuracy is 61.58% (p-value<1.00×10−3) with a cross-validation consistency of 10/10. Logistic regression analyses showed that the interaction for the effects of these two markers was statistically significant (p = 0.009) and the likelihood ratio test p value for including the interaction in the logistic regression model was 0.0072.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003283-g001: MDR complement and coagulation two locus model between FV and FVII.a. Testing accuracy and cross validation consistency for the best one to three locus models. b. Best multilocus model in the complement and coagulation pathway - Each multifactor cell is labeled as “high risk” or “low risk”. For each multifactor combination, hypothetical distributions of cases (left bar in cell) and controls (right bar in cell) are shown. Each cell represents a multilocus genotype; the genotype is labeled on the figure. The testing average balanced accuracy is 61.58% (p-value<1.00×10−3) with a cross-validation consistency of 10/10. Logistic regression analyses showed that the interaction for the effects of these two markers was statistically significant (p = 0.009) and the likelihood ratio test p value for including the interaction in the logistic regression model was 0.0072.
Mentions: Multilocus analyses on pathways with an excess of significant associations for either allele or genotype tests (identified by Z tests analyses) revealed a statistically significant two locus model in the complement and coagulation pathway in maternal data after excluding the single most significant tPA marker (rs879293) (Figure 1). This model included markers from Factor V and Factor VII with a balanced testing accuracy of 61.58% and a cross validation consistency of 10.

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