The magnitude of inflammatory response to an environmental stimulus can vary as a result of genotypic differences in cytokine and receptor genes. Since spontaneous preterm birth (SPTB) is a complex disorder induced by gene-environment interaction, we examined whether polymorphisms in cytokine genes play a role in SPTB either independently or in combination with bacterial vaginosis (BV).
From a prospective cohort of 3,160 asymptomatic gravidas, we conducted a nested case-control study of 119 women with SPTB at <37 weeks and 135 randomly selected controls with birth ≥37 weeks. DNA was extracted from cervicovaginal swabs. PCR with sequence-specific primers was applied to define 14 SNPs in genes encoding TNF, IL-2, IL-4, IL-6, IL-10, IL-12, and the IL-4 receptor (IL4R). BV was diagnosed on vaginal Gram stain obtained at 21-25 weeks′ if the Nugent score was ≥7. SNP alleles and genotypes were compared before and after stratification by race, BV, and type of PTB.
In the overall cohort the only SNPs associated with SPTB were rs2070874 in the promoter region of IL4 (T allele: OR 0.69; CI 0.48, 0.98) and rs1801275 in the coding region of IL4R (G allele: OR 0.54; 0.3, 0.98). Allele frequencies differed between African Americans (AA) (82% of patients) and Caucasians (P<0.0001). In AA, rs2070874 in was associated with SPTB at both the allele and genotype levels (T allele: OR 0.49; 0.27,0.88). The T allele was associated with even lower likelihood of SPTB in AA with BV (OR 0.19; 0.06, 0.66). rs4251960 in IL4 was also associated with SPTB in AA women with BV (T allele: OR 0.10; 0.04, 0.86). 68 cases were due to SPTL and 51 due to PROM. The IL4 rs2070874 was associated with SPTL (OR 0.49; 0.27, 0.89), but not PROM (OR 0.84; 0.44,1.62). Similarly, IL2 rs2069762 was associated with SPTL (OR 0.3; 0.1,0.9), but not PROM.
Several SNPs related to the IL-4 pathway are associated with the risk of spontaneous preterm birth, especially in the presence of BV, and may play more of a role in SPTL than PROM.
© 2008 Mosby, Inc. Published by Elsevier Inc. All rights reserved.