STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years.
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.
Department of Pulmonary & Allergy, University Children's Hospital Munich, LMU Munich, Munich, Germany.
V I
VI
Casaca
S
S
Illi
E
E
Klucker
N
N
Ballenberger
M
M
Schedel
E
E
von Mutius
M
M
Kabesch
B
B
Schaub
D000483:Alleles; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001991:Bronchitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002675:Child, Preschool; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood*; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007231:Infant, Newborn; D008297:Male; D063868:Patient Outcome Assessment; D020641:Polymorphism, Single Nucleotide; D050800:STAT6 Transcription Factor / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D015415:Biomarkers; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050800:STAT6 Transcription Factor; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human
STAT6; Tregs; atopy; neonates; polymorphisms