STAT6 - polymorphisms, haplotypes and epistasis in relation to atopy and asthma

Abstract

Background. STAT6 has an important role in the IL-4 / IL-13 signalling pathway. Genome -wide association studies have shown that particular polymorphism (SNP) or haplotype variants of STAT6 as well as epigenetic gene modifications are associated with IgE level and asthma in childhood. Methods. A review of the available literature was performed to map out the function and signalling pathway of STAT6, studies of STAT6 SNPs association with susceptibility to asthma and atopy, covering the years 1997 -2012 were summarized, and the value of epigenetic and epistatic influences on STAT6 and their relevance to the development of the studied phenotype (atopy or asthma) were determined. Results. There are 2 SNPs (rs71802646 and rs320411) with clinical association and proven functional effect on STAT6 expression. The effect of STAT6 SNPs cumulates in haplotypes and more potently during interaction with SNPs in the genes from the signalling pathway (IL4, IL4Ra, and IL13). Expression of STAT6 is also influenced by DNA methylation. Atopy is traditionally believed to be maternally inherited but there is one report about paternally overtransmitted STAT6 haplotype (TCA haplotype, built from rs324011, rs3024974 and rs4559 SNPs). Conclusions. STAT6 polymorphisms and their combinations have an important influence on IgE level and development of asthma. However, the interaction between SNPs in the IL-4 / IL-13 signalling pathway is of greater impact. Hypermethylation of the STAT6 promoter is also significant in the regulation of STAT6 expression and this fact opens possibilities for targeting therapy in asthma.

Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations

“…This was a new association reported by TAGC, not previously implicated in any asthma GWAS, although we note this SNP has been reported as a putatively causal SNP discovered by GWAS of lung function 23,24 , and a number of linkage studies have pinpointed this chromosomal region in the early days of genome-wide investigations of asthma and atopy 25–28 . In addition, markers in STAT6 have been identified by a number of candidate gene association studies 29–32 . However, prior to the CAAPA analyses, this locus had not been replicated in independent asthma GWAS datasets.…”

Analysis of changes in expression of IL-4/IL-13/STAT6 pathway and correlation with the selected clinical parameters in patients with atopic asthma

“…46 Moreover, STAT6 polymorphisms have an important influence on IgE level and development of asthma. 47 Lau et al 48 has suggested that loss of STAT6 promotes autoimmune disease and atopy and STAT6 correlates with IgE level.…”

Associations between STAT Gene Polymorphisms and Psoriasis in Northeastern China

“…rs7574865 has been associated with numerous autoimmune diseases, as well as with psoriasis in our investigation, indicating that the common functional sequences are shared in those autoimmune diseases and that rs7574865 plays an important role in the immune system and may represent a potential target for the treatment of these diseases [4,37] . STAT6 has similarity with other STAT proteins and is one of the most common candidate genes associated with higher levels of IgE [38] . STAT6 is essential for the functional responses of Th2 cells by inducing 2 forms of the cytokines IL-4 and IL-13 [39,40] .…”