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10: Hap-tag SNPs in genes that regulate the inflammatory response and bacterial vaginosis: evidence of gene-environment interactions associated with spontaneous preterm delivery

      Objective

      We demonstrated previously that genetic variation within genes that regulate the maternal inflammatory response are associated with an increased risk of spontaneous preterm delivery (SPTD). We sought to determine if an environmental exposure associated with maternal inflammation, bacterial vaginosis (BV), modifies these genetic susceptibilities.

      Study Design

      We conducted a prospective cohort study in which maternal DNA samples were collected from 744 women, and demographics and outcomes data were recorded. Vaginal smears for Gram-staining were obtained from subjects at 26-28 wk gestation. We studied hap-tag SNPs in 5 BioCarta and KEGG pathways in which >3 SNPs were strongly associated (P<0.01) with SPTD at <37 weeks (Illumina GoldenGate 1, 536-SNP custom chip panel). Associations between genotype distributions and SPTD were examined using Fisher's exact tests.

      Results

      In our cohort, 68 women experienced SPTD at <37 wk, while 676 women delivered at term (9.1% SPTD rate). 306 women had asymptomatic BV (Nugent score ≥7) at 26-28 wk, and BV was not associated with an increased risk of SPTD (P=0.30). 20 hap-tag SNPs were associated with an increased risk of SPTD (P<0.05) in the BV+ group. For 9 SNPs in 3 genes (FLT1, PRKCA, and IL6), the OR of SPTD ranged from 2.0-7.0 among BV+ women who were carriers of the rare allele, and the OR for SPTD were 2.0-5.0 times greater among BV+ women than among BV- women (P<0.05 for test of homogeneity between ORs).

      Conclusion

      These results demonstrate that the risk of SPTD associated with hap-tag SNPs in genes that regulate the maternal inflammatory response is modified by environmental exposures such as BV. Additional studies to identify functional SNPs within these hap-tag regions and potential mechanisms by which gene-environment interactions cause SPTD are warranted.
      Tabled 1Odds Ratios of SPTD for the minor allele in 3 hap-tag SNPs, stratified by BV status
      SNPGeneOR OverallOR BV (−)OR BV (+)
      rs17686640PRKCA2.5 (1.0,  6.2)2.0 (0.2,  17.0)7.0 (1.8,  26.4)
      rs1990503PRKCA2.0 (1.3,  3.2)0.8 (0.3,  2.6)4.0 (1.7,  9.0)
      rs1800795IL61.6 (1.1,  2.5)1.2 (0.6,  2.7)3.0 (1.4,  6.2)