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14: Identification of fetal and maternal single nucleotide polymorphisms in candidate genes that predispose to spontaneous preterm labor with intact membranes

      Objective

      Preterm labor/delivery can be caused by the activation of several pathologic pathways. A genetic association study was undertaken to determine whether the maternal and/or fetal carriage of single nucleotide polymorphisms (SNPs) in candidate genes predisposes to spontaneous preterm labor/delivery.

      Study Design

      A case-control study was conducted. Cases were patients with preterm labor who delivered <37 weeks. Controls consisted of women who delivered a normal AGA neonate at term; 190 candidate genes and 775 SNPs were studied. Cases were 223 mothers and 179 fetuses while controls consisted of 599 mothers and 628 fetuses. SNP discovery was performed by DNA sequencing, and genotyping was carried out using the MassARRAY(TM) System. Single locus and haplotype association analyses were performed separately on maternal and fetal DNA variants. Single locus tests of association were performed using logistic regression (additive model). We used a linkage disequilibrium based SNP pruning approach in the Plink software with a maximum r2 and a false discovery rate to correct for multiple testing (q*=0.15).

      Results

      1) The strongest fetal single locus association with spontaneous preterm birth was observed in the interleukin 6 receptor (IL6R) (OR=2.07 95% CI [1.42-3.02], p=0.000148); 2) The strongest maternal single locus association with spontaneous preterm labor/delivery was observed in a SNP in tissue inhibitor of metalloproteinase 2 (TIMP2) (OR=1.98 95% CI [1.38-2.83], p=0.000197); 3) These associations remain statistically significant after correction for multiple comparisons; 4) Global haplotype analysis indicated an association between a fetal DNA variant in insulin-like growth factor 2 (global p=0.004) and maternal alpha 3 type IV collagen isoform 1 (COL4A3, global p=0.007).

      Conclusion

      1) A SNP involved in the control of fetal inflammation (IL6R) doubled the risk of preterm birth; and 2) DNA variants in maternal genes encoding for proteins involved in extracellular matrix biology also increased the risk of preterm birth.