Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels

Schedel, Michaela; Michel, Sven; Gaertner, Vincent D.; Toncheva, Antoaneta A.; Depner, Martin; Binia, Aristea; Schieck, Maximilian; Rieger, Marie T.; Klopp, Norman; Berg, Andrea von; Bufe, Albrecht; Laub, Otto; Rietschel, Ernst; Heinzmann, Andrea; Simma, B; Vogelberg, Christian; Genuneit, Jon; Illig, Thomas; Kabesch, Michael

doi:10.1016/j.jaci.2015.03.014

Cited by 58 publications

(70 citation statements)

References 55 publications

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“…Remarkably, we found a loss of expression regulation depending on the haplotype during the activation process suggesting that other elements in the promoter, induced by the activation cascade, might acquire dominancy independent of the SNPs allelic variants. Similar results have been previously observed by others using PHA as an activator [10,11]. However, it has been also described that lymphocyte activation using Derp 1, an allergen of D .…”

Section: Discussionsupporting

confidence: 90%

“…Considering our calcium analysis data, we hypothesize that lymphocytes from haplotype B carriers might be more prone to differentiate to a Th2 subpopulation. Supporting this idea, the risk allele combination of this region has been previously associated with an increased production of Th2 cytokines[11]. …”

Section: Discussionmentioning

confidence: 87%

“…pteronyssinus , produces a differential gene expression within the region depending on the haplotype. All these data suggest a complex transcriptional control scenario of the 17q12-q21region linked to the stimulus applied and the pathways involved [11]. …”

Section: Discussionmentioning

confidence: 99%

“…SNPs located here are associated to Crohn’s disease, ulcerative colitis, ankylosing spondylitis, type I diabetes or rheumatoid arthritis [4–8]. Moreover, white blood cells counts [9], IL-17, IL-4 and IL-13 production [10,11] are also associated with SNPs present in this region. Thus, chromosome 17q12-q21 carries important genetic regulatory elements of the immune system.…”

Section: Introductionmentioning

confidence: 99%

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Lymphocyte Activation Dynamics Is Shaped by Hereditary Components at Chromosome Region 17q12-q21

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lymphocyte Activation Dynamics Is Shaped by Hereditary Components at Chromosome Region 17q12-q21

et al. 2016

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“…Numerous genome-wide association studies have linked ORMDL3 SNPs to increased risk of asthma development (32,33), while others have linked them to inflammatory disorders, including colitis, diabetes, and atherosclerosis (34,35). Therefore, we examined whether ORMDL expression is modulated physiologically during inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

ORMDL proteins regulate ceramide levels during sterile inflammation

Cai

Oyeniran

Biswas

et al. 2016

Journal of Lipid Research

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The GSDMB rs7216389 SNP is associated with chronic rhinosinusitis in a multi‐institutional cohort

Zack

Stern

Willis

et al. 2021

Int Forum Allergy Rhinol

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Background Chronic rhinosinusitis (CRS) is a multifactorial disease with a high co‐occurrence with asthma. In this multicohort study, we tested whether single nucleotide polymorphisms (SNPs) associated with childhood asthma and rhinovirus (RV)‐associated disease are related to an increased susceptibility to adult CRS in a multicohort retrospective case‐control study. Methods Participants at two tertiary academic rhinology centers, University of Arizona (UofA) and University of Pennsylvania (UPenn) were recruited. Cases were defined as those with physician diagnosed CRS (UofA, n = 149; UPenn, n = 250), and healthy controls were those without CRS (UofA, n = 66; UPenn, n = 275). Genomic DNA was screened for the GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP. Gene dosage, or the number of combined risk alleles in a single subject was calculated. Meta‐analysis of the association between GSDMB or CDHR3 genotypes and CRS was performed and additive gene dosage effect for each population calculated using p for trend. Results A meta‐analysis revealed a combined increased risk for CRS in subjects with the GSDMB rs7216389 SNP (odds ratio [OR] 1.40; 95% confidence interval [CI], 1.16–1.76; p = 0.004). Both the UofA (OR 1.73; 95% CI, 1.23–2.43; p = 0.002) and UPenn (OR 1.27; 95% CI, 1.02–1.58; p = 0.035) populations showed a significant positive association between the number of combined risk alleles of GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP and risk for CRS. Conclusion Carriers of the GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP are at increased susceptibility for CRS. These data suggest that therapeutic approaches to target aberrant responses to RV infection may play a role in the treatment of unified airway disease.

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Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels

Cited by 58 publications

References 55 publications

Lymphocyte Activation Dynamics Is Shaped by Hereditary Components at Chromosome Region 17q12-q21

Lymphocyte Activation Dynamics Is Shaped by Hereditary Components at Chromosome Region 17q12-q21

ORMDL proteins regulate ceramide levels during sterile inflammation

The GSDMB rs7216389 SNP is associated with chronic rhinosinusitis in a multi‐institutional cohort

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