STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years

Abstract

Background: The transcription factor STAT6 is crucial for activation of the interleukin (IL)-4/IL-13 pathway and has been linked to regulatory T cells (Tregs). Associations of STAT6 polymorphisms with IgE levels were described; however, their impact on neonatal immune responses and early disease development is unknown.

Methods: STAT6 polymorphisms were genotyped in cord blood mononuclear cells by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Gene expression was assessed by real-time polymerase chain reaction (PCR) and cytokines by Multiplex. At age 3 years, atopic diseases were assessed by questionnaires.

Results: STAT6 rs324011 but not rs1059513 polymorphism was associated with significant or borderline significant decreased mRNA expression of Treg-associated genes (FOXP3, GITR, LAG3). Heterozygotes and minor allele homozygotes of rs324011 had low levels of tumor necrosis factor alpha (TNF-α) and increased interferon gamma (IFN-γ) (P ≤ 0.04), while heterozygotes and minor allele homozygotes of rs1059513 had increased TNF-α and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (P ≤ 0.05). In minor allele homozygotes of rs324011, expression of Treg-associated genes was strongly inverse correlated with IFN-γ (unstimulated, r = -0.7, P = 0.111; LpA stimulation, r = -0.8, P = 0.011), but not in heterozygotes or major allele homozygotes. Heterozygotes and minor allele homozygotes of rs324011 presented a lower risk of atopic dermatitis and obstructive bronchitis until age 3 years.

Conclusions: Two STAT6 polymorphisms were associated with altered immune responses already at birth. STAT6 rs324011 was associated with lower neonatal Treg and increased Th1 response. Those neonates had a lower risk of atopic dermatitis and obstructive bronchitis until 3 years. Our data suggest a role for STAT6 polymorphisms in early immune regulation and implications on early atopic disease development.

Keywords: STAT6; Tregs; atopy; neonates; polymorphisms.