Biological and genetic interaction between Tenascin C and Neuropeptide S receptor 1 in allergic diseases

Neuropeptide S receptor 1 (NPSR1, GPRA 154, GPRA) has been verified as a susceptibility gene for asthma and related phenotypes. The ligand for NPSR1, Neuropeptide S (NPS), activates signalling through NPSR1 and microarray analysis has identified Tenascin C (TNC) as a target gene of NPS-NPSR1 signalling. TNC has previously been implicated as a risk gene for asthma. We aimed therefore to study the genetic association of TNC in asthma- and allergy-related disorders as well as the biological and genetic interactions between NPSR1 and TNC. Regulation of TNC was investigated using NPS stimulated NPSR1 transfected cells. We genotyped 12 TNC SNPs in the cross-sectional PARSIFAL study (3113 children) and performed single SNP association, haplotype association and TNC and NPSR1 gene-gene interaction analyses. Our experimental results show NPS-dependent upregulation of TNC-mRNA. The genotyping results indicate single SNP and haplotype associations for several SNPs in TNC with the most significant association to rhinoconjunctivitis for a haplotype, with a frequency of 29% in cases (P = 0.0005). In asthma and atopic sensitization significant gene-gene interactions were found between TNC and NPSR1 SNPs, indicating that depending on the NPSR1 genotype, TNC can be associated with either an increased or a decreased risk of disease. We conclude that variations in TNC modifies, not only risk for asthma, but also for rhinoconjunctivitis. Furthermore, we show epistasis based on both a direct suggested regulatory effect and a genetic interaction between NPSR1 and TNC. These results suggest merging of previously independent pathways of importance in the development of asthma- and allergy-related trait

The asthma candidate gene NPSR1 mediates isoform specific downstream signalling

Peer reviewe

Immune-microbiota interaction in Finnish and Russian Karelia young people with high and low allergy prevalence

Background After the Second World War, the population living in the Karelian region was strictly divided by the "iron curtain" between Finland and Russia. This resulted in different lifestyle, standard of living, and exposure to the environment. Allergic manifestations and sensitization to common allergens have been much more common on the Finnish compared to the Russian side. Objective The remarkable allergy disparity in the Finnish and Russian Karelia calls for immunological explanations. Methods Young people, aged 15-20 years, in the Finnish (n = 69) and Russian (n = 75) Karelia were studied. The impact of genetic variation on the phenotype was studied by a genome-wide association analysis. Differences in gene expression (transcriptome) were explored from the blood mononuclear cells (PBMC) and related to skin and nasal epithelium microbiota and sensitization. Results The genotype differences between the Finnish and Russian populations did not explain the allergy gap. The network of gene expression and skin and nasal microbiota was richer and more diverse in the Russian subjects. When the function of 261 differentially expressed genes was explored, innate immunity pathways were suppressed among Russians compared to Finns. Differences in the gene expression paralleled the microbiota disparity. High Acinetobacter abundance in Russians correlated with suppression of innate immune response. High-total IgE was associated with enhanced anti-viral response in the Finnish but not in the Russian subjects. Conclusions and clinical relevance Young populations living in the Finnish and Russian Karelia show marked differences in genome-wide gene expression and host contrasting skin and nasal epithelium microbiota. The rich gene-microbe network in Russians seems to result in a better-balanced innate immunity and associates with low allergy prevalence.Peer reviewe

Monitilatoimistojen sisäympäristö, käytettävyys ja tilan käyttäjien hyvinvointi (MOSI) : Tutkimushankkeen loppuraportti

Työterveyslaitoksen ja Helsingin yliopiston yhteistyössä tehdyssä tutkimushankkeessa (2014-2016) tutkittiin monitilaratkaisujen vaikutusta sisäilmastoon ja arvioitiin toteutettuja monitilaratkaisuja käytettävyyden, työn sisällön sekä terveyden ja hyvinvoinnin näkökulmista. Hankkeessa testattiin myös uusia hyvinvoinnin ja työympäristön arviointimenetelmiä. Monitilatoimistoratkaisuilla tavoiteltiin kustannussäätöjä, tilojen muuntojoustavuutta ja viihtyisyyttä sekä yhteisöllisyyttä, yhteistyötä eri yksiköiden ja yksilöiden välillä. Monitilatoimistoon siirtymisen koettiin parantaneen yhteisöllisyyttä ja vuorovaikutusta sekä lisänneen viihtyisyyttä ja tilatehokkuutta. Työrauhan arvioitiin heikentyneen. Toteutetut tilaratkaisut tukivat parhaiten hallinto-, asiantuntija- ja asiakaspalvelutyötä. Monitilatoimistoissa sisäilmasto oli pääosin hyvällä laatutasolla. Tiloissa, joissa oli tekstiilimatto ja useampia työpisteitä, mitatut sisäympäristön epäpuhtaustasot olivat pääsääntöisesti vähän korkeampia verrattuna perinteisiin huonetoimistoihin ja tiloihin, joissa oli linoleum-matto

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

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Astman alttiusgeenin, NPSR1:n, paikannettu kloonaus ja signaalireitti-analyysi

In the present study, we identified a novel asthma susceptibility gene, NPSR1 (neuropeptide S receptor 1) on chromosome 7p14.3 by the positional cloning strategy. An earlier significant linkage mapping result among Finnish Kainuu asthma families was confirmed in two independent cohorts: in asthma families from Quebec, Canada and in allergy families from North Karelia, Finland. The linkage region was narrowed down to a 133-kb segment by a hierarchial genotyping method. The observed 77-kb haplotype block showed 7 haplotypes and a similar risk and nonrisk pattern in all three populations studied. All seven haplotypes occur in all three populations at frequences > 2%. Significant elevated relative risks were detected for elevated total IgE (immunoglobulin E) or asthma. Risk effects of the gene variants varied from 1.4 to 2.5. NPSR1 belongs to the G protein-coupled receptor (GPCR) family with a topology of seven transmembrane domains. NPSR1 has 9 exons, with the two main transcripts, A and B, encoding proteins of 371 and 377 amino acids, respectively. We detected a low but ubiquitous expression level of NPSR1-B in various tissues and endogenous cell lines while NPSR1-A has a more restricted expression pattern. Both isoforms were expressed in the lung epithelium. We observed aberrant expression levels of NPSR1-B in smooth muscle in asthmatic bronchi as compared to healthy. In an experimental mouse model, the induced lung inflammation resulted in elevated Npsr1 levels. Furthermore, we demonstrated that the activation of NPSR1 with its endogenous agonist, neuropeptide S (NPS), resulted in a significant inhibition of the growth of NPSR1-A overexpressing stable cell lines (NPSR1-A cells). To determine which target genes were regulated by the NPS-NPSR1 pathway, NPSR1-A cells were stimulated with NPS, and differentially expressed genes were identified using the Affymetrix HGU133Plus2 GeneChip. A total of 104 genes were found significantly up-regulated and 42 down-regulated 6 h after NPS administration. The up-regulated genes included many neuronal genes and some putative susceptibility genes for respiratory disorders. By Gene Ontology enrichment analysis, the biological process terms, cell proliferation, morphogenesis and immune response were among the most altered. The expression of four up-regulated genes, matrix metallopeptidase 10 (MMP10), INHBA (activin A), interleukin 8 (IL8) and EPH receptor A2 (EPHA2), were verified and confirmed by quantitative reverse-transcriptase-PCR. In conclusion, we identified a novel asthma susceptibility gene, NPSR1, on chromosome 7p14.3. NPS-NPSR1 represents a novel pathway that regulates cell proliferation and immune responses, and thus may have functional relevance in the pathogenesis of asthma.Astma on keuhkoputkien limakalvojen tulehdussairaus, joka aiheuttaa keuhkojen toiminnan häiriöitä ja erityisesti keuhkoputkien ahtautumista. Astma on monitekijäinen sairaus, jonka syntyyn vaikuttavat useiden eri periytyvien alttiusgeenien ja ympäristötekijöiden vuorovaikutus. Suomessa arviolta 6% väestöstä sairastaa astmaa. Astma on yleisin lääkitystä vaativa pitkäaikaissairaus lapsilla. Tutkimuksessamme löysimme uuden astmalle altistavan geenin, NPSR1:n (neuropeptidi S reseptori 1). Löydöksemme pohjautuu aiempaan tutkimukseeme, koko genomin kattavaan geenihakuun (kytkentäanalyysi), jossa paikansimme kainuulais-potilailta astmalle altistavan alueen kromosomista 7. Tässä väitöstutkimuksessa osoitimme NPSR1:n riskivaikutuksen myös kahdessa muussa potilasaineistossa: pohjoiskarjalaisilla ja kanadan-ranskalaisilla perheillä. Osoitimme, että riski sairastua astmaan on 1.4-2.5 kertainen geenin riskimuotoa kantavilla potilailla verrrattuna muuhun väestöön. NPSR1-proteiini kuuluu rakenteensa perusteella G-proteiinireseptoreihin, jotka toimivat solukalvolla välittäen signaaleja solun sisäpuolelle. Tutkimme NPSR1:n ilmentymistä ja osoitimme, että NPSR1 ilmenee useissa erityyppisissä soluissa ja kudoksissa, kuten keuhkojen ja ruoansulatuskanavan limakalvoilla sekä iholla. Osoitimme kudosvärjäyksin, että astmaa sairastavilla potilailla NPSR1:n määrä keuhkojen sileässä lihaksessa kasvoi terveisiin verrokkeihin verrattuna. Lisäksi osoitimme hiirimallilla, että aiheutettu astman kaltainen keuhkotulehdus johti NPSR1:n märän kasvuun hiiren keuhkoissa. NPSR1:n toiminnasta saimme solumallia käyttäen selville, että NPSRI säätelee solukasvua. Edelleen tutkimme mikrosirutekniikalla, mitkä ovat NPSR1:n kohdegeenejä. Stimuloimme NPSR1:tä ylituottavat solut spesifisellä neuropeptidi S ligandilla (NPS) ja määritimme kohdegeenien ilmentymisen 6 tuntia stimulaation jälkeen. Tunnistimme 104 geeniä, joiden ilmentyminen oli kasvanut, sekä 42 geeniä, joiden ilmentyminen oli laskenut. NPSR1:n säätelemien geenien joukossa oli mm. muutamia neuronaalisia geenejä sekä hengitystiesairauksien mahdollisia alttiusgeenejä. Analysoimme mitä toimintoja kohdegeenit säätelevät, ja tärkeimmät ryhmät olivat immuunivasteet, morfologia ja proliferaatio (solukasvun säätely). Yhteenvetona todettakoon, että tässä tutkimuksessa löysimme uuden astmalle altistavan geenin, NPSR1:n, jonka proteiinituote kuuluu G-proteiinireseptoreihin. Tämäntyyppiset solukalvon reseptorit ovat yleisiä lääkekohdemolekyylejä, ja siten myös NPSR1:lle on teoriassa mahdollista kehittää lääkeaine, kunhan NPS-NPSR1 -signaalireitin vaikutukset astman syntyyn tunnetaan paremmin

Biological and genetic interaction between tenascin C and neuropeptide S receptor 1 in allergic diseases

Neuropeptide S receptor 1 (NPSR1, GPRA 154, GPRA) has been verified as a susceptibility gene for asthma and related phenotypes. The ligand for NPSR1, Neuropeptide S (NPS), activates signalling through NPSR1 and microarray analysis has identified Tenascin C (TNC) as a target gene of NPS-NPSR1 signalling. TNC has previously been implicated as a risk gene for asthma. We aimed therefore to study the genetic association of TNC in asthma- and allergy-related disorders as well as the biological and genetic interactions between NPSR1 and TNC. Regulation of TNC was investigated using NPS stimulated NPSR1 transfected cells. We genotyped 12 TNC SNPs in the cross-sectional PARSIFAL study (3113 children) and performed single SNP association, haplotype association and TNC and NPSR1 gene-gene interaction analyses. Our experimental results show NPS-dependent upregulation of TNC-mRNA. The genotyping results indicate single SNP and haplotype associations for several SNPs in TNC with the most significant association to rhinoconjunctivitis for a haplotype, with a frequency of 29% in cases (P = 0.0005). In asthma and atopic sensitization significant gene-gene interactions were found between TNC and NPSR1 SNPs, indicating that depending on the NPSR1 genotype, TNC can be associated with either an increased or a decreased risk of disease. We conclude that variations in TNC modifies, not only risk for asthma, but also for rhinoconjunctivitis. Furthermore, we show epistasis based on both a direct suggested regulatory effect and a genetic interaction between NPSR1 and TNC. These results suggest merging of previously independent pathways of importance in the development of asthma- and allergy-related traits

The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus

Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin-dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE). Material an