Risk of small-for-gestational age is associated with common anti-inflammatory cytokine polymorphisms

Background: Anti-inflammatory cytokines play a key role in pregnancy maintenance. Genetic variation in anti-inflammatory cytokines could influence a woman's risk of adverse reproductive outcomes. Methods: We investigated the relationship of polymorphisms in interleukin 4 (IL4), IL5, IL10, IL13, and transforming growth factor (TGFβ1) with spontaneous preterm birth and small-for-gestational age (SGA) in a nested case-control study of a prospective pregnancy cohort. Women were recruited between 24 and 29 weeks' gestation at the Wake County and University of North Carolina, Ghapel Hill obstetric clinics between February 1996 and June 2000. We inferred haplotypes using the EM algorithm and the Bayesian method, PHASE. Semi-Bayesian hierarchical logistic regression was used to obtain odds ratio (OR) estimates and 95% confidence intervals (CIs) for each polymorphism. Results: African-American mothers who carried the IL4 GCC haplotype had greater risk of spontaneous preterm birth (OR = 2.9; 95% CI = 1.2-7.4). In white mothers, carriers of the "low- producing" IL4 CC and IL10 ATA haplotypes had markedly reduced risk of SGA (for the CC haplotype, 0.2 [0.0-1.2]; for the ATA haplotype, 0.5 [0.3-0.8]), whereas carriers of the "high-producing" IL4(-589)T variant had increased risk of SGA in both African-American and white mothers. Conclusions: Variants related to decreased anti-inflammatory cytokine production may lower risk of SGA. Furthermore, the same mechanism that protects against SGA might increase risk of spontaneous preterm birth.