Abstract
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 = 2.0×10−6) 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.
Highlights
Preterm birth (,37 weeks gestation—PTB) accounts for 12.0– 13.0% of pregnancies in the United States [1,2] and the rate in Caucasians has been trending upward in the last decade [3,4]
The single most significant association was seen in tissue plasminogen activator (tPA) at rs879293 with a case minor allele frequency (MAF) = 0.35 and a control MAF = 0.46
Six of the eight single nucleotide polymorphisms (SNPs) genotyped in tPA had a statistically significant single locus allelic and/or genotypic association, but the other SNPs failed to hold up to a Bonferroni correction
Summary
Preterm birth (,37 weeks gestation—PTB) accounts for 12.0– 13.0% of pregnancies in the United States [1,2] and the rate in Caucasians has been trending upward in the last decade [3,4]. PTB is associated with a 40-fold increase in neonatal morbidity and mortality [5,6,7]. History of PTB [9,11,12,13,14], twin studies that estimated heritability between 20 and 40%, [15,16], and association between ethnicity/race and PTB [11,17] support this conclusion. These data are not conclusive, they do suggest that genetic variation influences PTB susceptibility
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