title: Preterm birth in Caucasians is associated with coagulation and inflammation pathway gene variants.
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.
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.
authors.forename: Digna R
authors.initials: DR
authors.lastname: Velez
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Fortunato
authors.forename: Poul
authors.initials: P
authors.lastname: Thorsen
authors.forename: Salvatore J
authors.initials: SJ
authors.lastname: Lombardi
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D005165:Factor V / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics; D008954:Models, Biological; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D053709:Interleukin-10 Receptor alpha Subunit; D005165:Factor V; D010959:Tissue Plasminogen Activator