Interaction between Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA) and Neuropeptide S Receptor 1 (NPSR1) in Asthma

Acevedo, Nathalie; Sääf, Annika; Söderhäll, Cilla; Melén, Erik; Mandelin, Jami; Orsmark-Pietras, Christina; Ezer, Sini; Karisola, Piia; Vendelin, Johanna; Gennäs, Gustav Boije af; Yli‐Kauhaluoma, Jari; Alenius, Harri; Mutius, Erika von; Doekes, Gert; Braun‐Fahrländer, Charlotte; Riedler, Josef; Hage, Marianne van; D’Amato, Mauro; Scheynius, Annika; Pershagen, Göran; Kere, Juha; Pulkkinen, Ville

doi:10.1371/journal.pone.0060111

Cited by 27 publications

(44 citation statements)

References 66 publications

(71 reference statements)

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“…The children were examined and blood samples were taken at 4 and/or 8 y of age. DNA was available from 2033 subjects collected at 8 y of age (33). Subjects diagnosed with asthma at any follow-up from 1 to 16 y were considered as asthma cases (n = 440, of which 300 are also allergy cases) and healthy, nonasthmatic, nonallergic as controls (n = 839).…”

Section: Bamse Samplesmentioning

confidence: 99%

GIMAP GTPase Family Genes: Potential Modifiers in Autoimmune Diabetes, Asthma, and Allergy

Heinonen¹,

Laine

Söderhäll

et al. 2015

The Journal of Immunology

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GTPase of the immunity-associated protein (GIMAP) family members are differentially regulated during human Th cell differentiation and have been previously connected to immune-mediated disorders in animal studies. GIMAP4 is believed to contribute to the Th cell subtype–driven immunological balance via its role in T cell survival. GIMAP5 has a key role in BB-DR rat and NOD mouse lymphopenia. To elucidate GIMAP4 and GIMAP5 function and role in human immunity, we conducted a study combining genetic association in different immunological diseases and complementing functional analyses. Single nucleotide polymorphisms tagging the GIMAP haplotype variation were genotyped in Finnish type 1 diabetes (T1D) families and in a prospective Swedish asthma and allergic sensitization birth cohort. Initially, GIMAP5 rs6965571 was associated with risk for asthma and allergic sensitization (odds ratio [OR] 3.74, p = 0.00072, and OR 2.70, p = 0.0063, respectively) and protection from T1D (OR 0.64, p = 0.0058); GIMAP4 rs13222905 was associated with asthma (OR 1.28, p = 0.035) and allergic sensitization (OR 1.27, p = 0.0068). However, after false discovery rate correction for multiple testing, only the associations of GIMAP4 with allergic sensitization and GIMAP5 with asthma remained significant. In addition, transcription factor binding sites surrounding the associated loci were predicted. A gene–gene interaction in the T1D data were observed between the IL2RA rs2104286 and GIMAP4 rs9640279 (OR 1.52, p = 0.0064) and indicated between INS rs689 and GIMAP5 rs2286899. The follow-up functional analyses revealed lower IL-2RA expression upon GIMAP4 knockdown and an effect of GIMAP5 rs2286899 genotype on protein expression. Thus, the potential role of GIMAP4 and GIMAP5 as modifiers of immune-mediated diseases cannot be discarded.

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Section: Bamse Samplesmentioning

confidence: 99%

GIMAP GTPase Family Genes: Potential Modifiers in Autoimmune Diabetes, Asthma, and Allergy

Heinonen¹,

Laine

Söderhäll

et al. 2015

The Journal of Immunology

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“…Furthermore, polymorphism in NPSR1 was associated with bedtime and sleepiness in a genome-wide association study [48]. Motivated by these findings, we previously showed that NPS affects circadian clock gene expression in the same SH-SY5Y cell line with NPSR1 overexpression [35]. Of these genes that regulate circadian molecular clock machinery, NPAS2 , PER1 , CRY1 , and RORA were among the most affected genes in the current microarray experiment.…”

Section: Discussionmentioning

confidence: 71%

“…After 24 h, the cells were transfected with recombinant full-length NPSR1 constructs fused with either red fluorescence protein (NPSR1-A-pDsRed) or green fluorescent protein (NPSR1-B-GFP) using 1.3 μl Fugene HD and 0.5 μg of DNA per well. Construction of the expression vectors has been described earlier [35]. After 24 h, the cells were fixed with 4 % paraformaldehyde in phosphate-buffered saline (PBS) for 5 min.…”

Section: Methodsmentioning

confidence: 99%

Neuropeptide S receptor 1 (NPSR1) activates cancer-related pathways and is widely expressed in neuroendocrine tumors

et al. 2014

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Neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells and express general and specific neuroendocrine markers. Neuropeptide S receptor 1 (NPSR1) is expressed in neuroendocrine cells and its ligand neuropeptide S (NPS) affects cell proliferation. Our aim was to study whether NPS/NPSR1 could be used as a biomarker for neuroendocrine neoplasms and to identify the gene pathways affected by NPS/NPSR1. We collected a cohort of NETs comprised of 91 samples from endocrine glands, digestive tract, skin, and lung. Tumor type was validated by immunostaining of chromogranin-A and synaptophysin expression and tumor grade was analyzed by Ki-67 proliferation index. NPS and NPSR1 expression was quantified by immunohistochemistry using polyclonal antibodies against NPS and monoclonal antibodies against the amino-terminus and carboxy-terminus of NPSR1 isoform A (NPSR1-A). The effects of NPS on downstream signaling were studied in a human SH-SY5Y neuroblastoma cell line which overexpresses NPSR1-A and is of neuroendocrine origin. NPSR1 and NPS were expressed in most NET tissues, with the exception of adrenal pheochromocytomas in which NPS/NPSR1 immunoreactivity was very low. Transcriptome analysis of NPSR1-A overexpressing cells revealed that mitogen-activated protein kinase (MAPK) pathways, circadian activity, focal adhesion, transforming growth factor beta, and cytokine–cytokine interactions were the most altered gene pathways after NPS stimulation. Our results show that NETs are a source of NPS and NPSR1, and that NPS affects cancer-related pathways.Electronic supplementary materialThe online version of this article (doi:10.1007/s00428-014-1602-x) contains supplementary material, which is available to authorized users.

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“…Thus, ignoring epistatic effects may mask important genetic susceptibility. While other studies have utilized biologic plausibility 51, 52 , results from linkage analyses 53, 54 and bioinformatics 54, 55 to inform analyses of genetic interactions in asthma, our study is the first to apply this approach in an independent population and replicate findings where no significant independent effects were observed (blacks).…”

Section: Discussionmentioning

confidence: 91%

Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma

Myers

Martin

Kovacic

et al. 2014

Journal of Allergy and Clinical Immunology

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Background Epithelial genes have previously been associated with asthma, but only explain a small fraction of heritability. In part, this may be due to epistasis that is often not considered. Objective To determine independent and epistatic associations between FLG, SPINK5 and TSLP gene variants and childhood asthma. Methods Using a candidate gene approach, we genotyped 29 variants in FLG, SPINK5 and TSLP in asthmatic, allergic, and non-allergic-non-asthmatic white and black children participating in the well-phenotyped Greater Cincinnati Pediatric Clinic Repository (GCPCR). Associations with asthma were also assessed in six replication populations. Results We observed independent associations of variants in SPINK5 (p=0.003) and TSLP (p=0.006) with childhood asthma; a SPINK5 SNP was replicated. In subjects with one or more SPINK5 risk alleles, the absence of the TSLP protective minor alleles was associated with a significant increase in asthma (67% vs. 53%, p=0.0017). In contrast, the presence or absence of TSLP minor alleles did not affect asthma risk in subjects without the SPINK5 risk alleles. The SPINK5 and TSLP epistasis was replicated in a black population (p=0.036) that did not display independent association with variants in these genes. Conclusions Our results support epistasis between SPINK5 and TSLP which contributes to childhood asthma. These findings emphasize the importance of utilizing biology to inform analyses to identify genetic susceptibility to complex diseases. The results from our study have clinical relevance and support that the therapeutic effects of anti-TSLP therapy in asthmatics may be dependent on SPINK5 genotype.

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Interaction between Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA) and Neuropeptide S Receptor 1 (NPSR1) in Asthma

Cited by 27 publications

References 66 publications

GIMAP GTPase Family Genes: Potential Modifiers in Autoimmune Diabetes, Asthma, and Allergy

GIMAP GTPase Family Genes: Potential Modifiers in Autoimmune Diabetes, Asthma, and Allergy

Neuropeptide S receptor 1 (NPSR1) activates cancer-related pathways and is widely expressed in neuroendocrine tumors

Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma

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