Birth order modifies the effect of Interleukin-13 (IL13) gene polymorphisms on total serum IgE and skin prick test at ages 4, 10 and 18: A prospective birth cohort study

Background: The prenatal and post-natal environments may affect gene expression. Birth order has been identified as a risk factor for atopy, but the mechanistic evidence is still inconclusive. Objective: To investigate the interaction of IL13 polymorphisms with birth order on allergic sensitization. Methods: Mother-infant dyads were pre-natally recruited at the Isle of Wight. Data from questionnaires, skin prick tests (SPT), serum IgE (sIgE) and inhalant specific IgE screen (inhIgE), and IL13 genotyping were collected prospectively. Three IL13 SNPs were selected: rs20451 (nonsynonymous), rs1800925 (promoter) and rs2066960 (intron). Results: Birth order data was available for 83.2% (1212/1456); SPT was performed on 67.4%, 71.2% and 58.0% at ages 4, 10 and 18 respectively. The prevalence of atopy (sensitization to one or more food or aeroallergens) increased from 19.7% at age 4, to 26.7% at 10 and 41.1% at 18 years. Multivariable repeated measurement regression analysis indicated interaction between rs20541 and birth order on SPT. On stratification, the effect of IL13 on SPT was restricted only to first-born children (p=0.007; adjusted prevalence ratios [PR]=1.35; 95%CI=1.09, 1.69). Similar findings were noted at age 10 for first-order births for sIgE (p=0.007; PR=1.73; 95%CI=1.16, 2.57) and inhIgE (p=0.034; PR=1.48; 95%CI=1.03, 2.13). Conclusions: This is the first study to show an interaction between birth order and IL13 polymorphisms on allergic sensitization in late childhood. This effect modification may partly explain the mechanism of the birth order effect: IL13 may undergo epigenetic changes in utero due to conditions specific to a first pregnancy compared to subsequent pregnancies.