Abstract
Single nucleotide polymorphisms (SNPs) located in the chromosome region 17q12-q21 are risk factors for asthma. Particularly, there are cis-regulatory haplotypes within this region that regulate differentially the expression levels of ORMDL3, GSDMB and ZPBP2 genes. Remarkably, ORMDL3 has been shown to modulate lymphocyte activation parameters in a heterologous expression system. In this context, it has been shown that Th2 and Th17 cytokine production is affected by SNPs in this region. Therefore, we aim to assess the impact of hereditary components within region 17q12-q21 on the activation profile of human T lymphocytes, focusing on the haplotype formed by allelic variants of SNPs rs7216389 and rs12936231. We measured calcium influx and activation markers, as well as the proliferation rate upon T cell activation. Haplotype-dependent differences in mRNA expression levels of IL-2 and INF-γ were observed at early times after activation. In addition, the allelic variants of these SNPs impacted on the extent of calcium influx in resting lymphocytes and altered proliferation rates in a dose dependent manner. As a result, the asthma risk haplotype carriers showed a lower threshold of saturation during activation. Finally, we confirmed differences in activation marker expression by flow cytometry using phytohemagglutinin, a strong polyclonal stimulus. Altogether, our data suggest that the genetic component of pro-inflammatory pathologies present in this chromosome region could be explained by different T lymphocyte activation dynamics depending on individual allelic heredity.
Highlights
The genetic component behind the susceptibility of some individuals to certain diseases is based on polymorphisms within the human genome that can modify the function and/or the expression levels of one or more genes
In order to experimentally define this haplotype in linkage disequilibrium we chose the Single Nucleotide Polymorphisms (SNPs) rs7216389, the first asthma associated SNP described in this region [1], and rs12936231, an evolutionary conserved SNP whose allelic variants have been postulated to contribute to alternative conformations of the chromosome region 17q12-q21 [2]
We evaluated the expression of different genes of this region in human lymphocytes under resting and activation conditions depending on haplotypes defined by the allele combination of these two SNPs: haplotype A were homozygous G and C carriers, and haplotype B were homozygous C and T carriers
Summary
The genetic component behind the susceptibility of some individuals to certain diseases is based on polymorphisms within the human genome that can modify the function and/or the expression levels of one or more genes. Genome Wide Association Studies (GWAS) search for unbalanced distributions of allelic frequencies of Single Nucleotide Polymorphisms (SNPs) that point out novel genes associated to complex diseases. These SNPs often do not locate within coding regions, but map to cis regulatory elements that affect expression levels of genes surrounding them. This is the case for Orosomucoid-like 3 (ORMDL3), a member of the orosomucoid-like protein family (ORMDL) associated to childhood asthma [1]. Various SNPs in the same chromosome region 17q12-q21 form a cis regulatory haplotype in linkage disequilibrium that determines, by altering nucleosome enrichment and methylation, the expression of adjacent genes such as IKAROS Family Zinc Finger 3 (IKZF3), Zona Pellucida Binding Protein 2 (ZPBP2), GSDMB and ORMDL3[2,3]
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