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 3 (9): e3283

PMID: 18818748 · PMCID: PMC2553267 · DOI:10.1371/journal.pone.0003283

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.

MeSH Terms (15)

Adolescent Adult Case-Control Studies European Continental Ancestry Group Factor V Female Genetic Predisposition to Disease Genetic Variation Humans Inflammation Interleukin-10 Receptor alpha Subunit Models, Biological Pregnancy Premature Birth Tissue Plasminogen Activator

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