4.2 Variation in Beta Defensin 1 Genotype is Associated with Preterm Birth

Abstract

Introduction Human beta defensin 1 (HBD1) is an antimicrobial and immunomodulatory peptide present in cervical mucus. Variation in cervical antimicrobial expression is associated with preterm labour. We hypothesized that SNPs in the HBD1 gene may be associated with preterm birth. Methods This is a retrospective case control study. Genomic DNA was extracted from blood collected at 11-13 weeks from women attending King's College Hospital March 2006-September 2010. 50 women with premature prelabour rupture of membranes (PPROM) in the index pregnancy and 50 with spontaneous preterm labour were matched (ethnicity, smoking, BMI) with 300 who delivered at term. The SNPs rs1799946 (5'UTR) and rs1047031 (3'UTR) were genotyped by KASP assay (Kompetitive Allele Specific PCR, KBioscience). Data were analysed using multiplicative (rs1047031) and recessive (rs1799946) models and Chi Square Test, and were assessed for Hardy-Weinberg equilibrium. Results There was no difference in BMI, smoking status or ethnicity between the groups. Genotyping was successful in 98% (n=390) samples for rs1047031 and 97% for rs1799946 (n=386). Allele distribution in controls demonstrated Hardy-Weinberg equilibrium. AA homozygotes (rs1799946) had a significantly increased risk of PPROM; OR 2.24 (95%CI 1.11-4.49), p=0.0.0257. No association was seen with spontaneous preterm labour. Of the 400 women, 117 had at least one prior delivery before 37 weeks and 36 had a history of delivery before 28 weeks. AA homozygotes (rs1799946) had significantly increased risk of delivery before 37 weeks; OR 2.14 (95%CI 1.24-3.68), p=0.005 and an even higher risk of delivery before 28 weeks; OR 4.08 (95%CI 1.93-8.63), p<0.0001. Carriers of the A allele (rs1047031) were less likely to deliver before 28 weeks; OR 0.288 (95%CI 0.121-0.683), p=0.003. In this combined analysis clinical data was not available to differentiate between prior history of PPROM and spontaneous preterm labour. Conclusion rs1799946 is associated with PPROM, a doubled risk of delivery before 37 weeks and a four-fold increase in the risk of delivery before 28 weeks. rs1047031 may be protective. These data suggest that variation in innate immune genotype may contribute to the clinical phenotype of women who deliver preterm.