Document Detail

Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma.
Jump to Full Text
MedLine Citation:
PMID:  21244681     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Allergic rhinitis (AR) affects up to 80% of children with asthma and increases asthma severity. Thymic stromal lymphopoietin (TSLP) is a key mediator of allergic inflammation. The role of the TSLP gene (TSLP) in the pathogenesis of AR has not been studied.
OBJECTIVE: To test for associations between variants in TSLP, TSLP-related genes, and AR in children with asthma.
METHODS: We genotyped 15 single nucleotide polymorphisms (SNPs) in TSLP, OX40L, IL7R, and RXRα in three independent cohorts: 592 asthmatic Costa Rican children and their parents, 422 nuclear families of North American children with asthma, and 239 Swedish children with asthma. We tested for associations between these SNPs and AR. As we previously reported sex-specific effects for TSLP, we performed overall and sex-stratified analyses. We additionally performed secondary analyses for gene-by-gene interactions.
RESULTS: Across the three cohorts, the T allele of TSLP SNP rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone. The SNP was associated with reduced odds for AR (odds ratios ranging from 0.56 to 0.63, with corresponding Fisher's combined P value of 1.2 × 10-4). Our findings were significant after accounting for multiple comparisons. SNPs in OX40L, IL7R, and RXRα were not consistently associated with AR in children with asthma. There were nominally significant interactions between gene pairs.
CONCLUSIONS: TSLP SNP rs1837253 is associated with reduced odds for AR in boys with asthma. Our findings support a role for TSLP in the pathogenesis of AR in children with asthma.
Authors:
Supinda Bunyavanich; Erik Melen; Jemma B Wilk; Mark Granada; Manuel E Soto-Quiros; Lydiana Avila; Jessica Lasky-Su; Gary M Hunninghake; Magnus Wickman; Göran Pershagen; George T O'Connor; Scott T Weiss; Juan C Celedón
Publication Detail:
Type:  Journal Article     Date:  2011-01-18
Journal Detail:
Title:  Clinical and molecular allergy : CMA     Volume:  9     ISSN:  1476-7961     ISO Abbreviation:  Clin Mol Allergy     Publication Date:  2011  
Date Detail:
Created Date:  2011-02-03     Completed Date:  2011-08-17     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  101152195     Medline TA:  Clin Mol Allergy     Country:  England    
Other Details:
Languages:  eng     Pagination:  1     Citation Subset:  -    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Grant Support
ID/Acronym/Agency:
K08 HL092222/HL/NHLBI NIH HHS; K08 HL092222-04/HL/NHLBI NIH HHS; K12 HL089990-05/HL/NHLBI NIH HHS; R00 HL096840-03/HL/NHLBI NIH HHS
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Clin Mol Allergy
ISSN: 1476-7961
Publisher: BioMed Central
Article Information
Download PDF
Copyright ©2011 Bunyavanich et al; licensee BioMed Central Ltd.
open-access:
Received Day: 27 Month: 10 Year: 2010
Accepted Day: 18 Month: 1 Year: 2011
collection publication date: Year: 2011
Electronic publication date: Day: 18 Month: 1 Year: 2011
Volume: 9First Page: 1 Last Page: 1
ID: 3032752
Publisher Id: 1476-7961-9-1
PubMed Id: 21244681
DOI: 10.1186/1476-7961-9-1

Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma
Supinda Bunyavanich125 Email: supinda@post.harvard.edu
Erik Melen1567 Email: erik.melen@channing.harvard.edu
Jemma B Wilk9 Email: jwilk@bu.edu
Mark Granada10 Email: Mark.Granada@bmc.org
Manuel E Soto-Quiros12 Email: msotoq@hnn.sa.cr
Lydiana Avila12 Email: lydiana98@gmail.com
Jessica Lasky-Su15 Email: jessica.su@channing.harvard.edu
Gary M Hunninghake135 Email: ghunninghake@partners.org
Magnus Wickman68 Email: magnus.wickman@ki.se
Göran Pershagen6 Email: Goran.Pershagen@ki.se
George T O'Connor1011 Email: goconnor@bu.edu
Scott T Weiss145 Email: scott.weiss@channing.harvard.edu
Juan C Celedόn1345131415 Email: juan.celedon@chp.edu
1Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
2Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
3Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
4Center for Genomic Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
5Harvard Medical School, Boston, Massachusetts, USA
6Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
7Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
8Sachs Children's Hospital, Stockholm, Sweden
9Department of Neurology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
10Pulmonary Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
11The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA
12Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica
13Division of Pulmonary Medicine, Allergy, and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
14Department of Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
15Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA

Introduction

Allergic rhinitis (AR) is a common chronic disease, affecting 10-30% of adults and 40% of children [1]. Characterized by nasal congestion, itching, rhinorrhea, and sneezing, AR decreases school and work productivity. AR is a risk factor for asthma exacerbations and asthma-related hospitalization [2,3]. Up to 80% of children with asthma have AR [4], and treatment of comorbid AR reduces the odds of asthma-related healthcare by up to 80% [5]. A better understanding of the pathophysiology of AR could decrease morbidity in asthmatics and in children overall.

The role of thymic stromal lymphopoietin (TSLP) in the pathogenesis of AR has not been extensively studied. TSLP is an interleukin (IL)-7-like cytokine that triggers dendritic cells and mast cells to induce T helper (Th)2 inflammatory responses (Figure 1) [6,7]. The gene for TSLP (TSLP) is expressed by epithelial cells of the lung, skin and gut [8]. In humans, TSLP has been linked to the pathogenesis of asthma [9-11], atopic dermatitis [6], and eosinophilic esophagitis [12]. A few in vitro and murine studies with small sample size have examined TSLP expression in allergic rhinitis (AR) [13-16]. To date, there have been no genetic association studies of TSLP and AR.

The effects of TSLP are influenced by its heterodimeric receptor, costimulatory molecules, transcriptional regulators, and other cytokines (Figure 1). Therefore, we were also interested in examining the association between AR and genes related to TSLP, including OX40L, IL7R, and RXRα. Expressed by antigen-presenting cells, OX40L is an essential costimulatory mediator of TSLP-mediated Th2 responses [17,18]. Blockade of OX40L inhibits TSLP-driven Th2 inflammatory cell infiltration, cytokine secretion, and IgE production in mouse lung and skin [19]. The receptor for TSLP is a heterodimeric complex composed of TSLPR and IL7Rα chains [20]. The TSLPR chain binds to TSLP at low affinity but its combination with the IL7Rα chain results in high-affinity binding and STAT5 activation [21,22]. The IL7Rα chain is encoded by IL7R. The nuclear receptors retinoid × receptor (RXR)α and RXRβ act as transcriptional repressors that inhibit TSLP gene expression in mouse skin keratinocyte models of atopic dermatitis [23].

In this study, we report an analysis of association between single nucleotide polymorphisms (SNPs) in TSLP, OX40L, IL7R, and RXRα and AR in three independent studies of children with asthma from Costa Rica, North America, and Sweden. We chose to perform this study in children with asthma because AR causes disproportionately high morbidity in children with asthma, and AR is up to four times more prevalent in children with asthma [24]. We found that a SNP in TSLP was associated with reduced odds for AR in boys across the three cohorts of children with asthma.


Methods
Ethics Statement

Written informed consent was obtained from study participants and from parents of children in the cohorts. The institutional review boards of Brigham & Women's Hospital, CAMP Study Centers, and Karolinska Institutet approved the study protocols.

Study Populations
The Genetics of Asthma in Costa Rica

The Genetics of Asthma in Costa Rica study includes 616 children ages 6-14 years with asthma who were recruited between February 2001 and March 2006 [4]. This population is a genetic isolate of mixed Spanish and Amerindian descent with one of the world's highest rates of asthma (27.4% of children aged 6-7 years [25]). Questionnaires were sent to the parents of 13,125 schoolchildren enrolled in 113 schools in Costa Rica. Of the 7,282 children whose parents returned questionnaires, 2,714 had asthma (defined as physician-diagnosed asthma and ≥2 respiratory symptoms or recurrent asthma attacks in the past year). Of these 2,714 children, 616 had high probability of having ≥6 great-grandparents born in the Central Valley of Costa Rica (to ensure descent from the founder population), and were willing to participate along with their parents. Of these 616 parent-child trios, 24 were excluded because of inadequate DNA quality, leaving 592 trios for genotyping and analysis.

Childhood Asthma Management Program (CAMP)

CAMP is a multicenter North American clinical trial designed to investigate the long-term effects of inhaled anti-inflammatory medications in children with mild to moderate asthma [26]. Participating children had asthma defined by symptoms greater than 2 times per week, use of an inhaled bronchodilator at least twice weekly or use of daily medication for asthma, and increased airway responsiveness to methacholine (PC20 ≤ 12.5 mg/ml). Children with severe asthma or other clinically significant medical conditions were excluded. Of the 1041 children enrolled in the original clinical trial, 968 children and 1518 of their parents contributed DNA samples to the CAMP Genetics Ancillary Study [27]. Selection criteria for genome wide association study (GWAS) genotyping were (a) self-described non-Hispanic white ethnicity and (b) availability of sufficient DNA for microarray hybridization; 422 children and their parents met these criteria.

Children, Allergy, Milieu, Stockholm, Epidemiological Survey (BAMSE)

BAMSE is a birth cohort study of allergy and environment. 4089 newborn infants were recruited between 1994 and 1996 from central and northwestern parts of Stockholm, Sweden [28]. At eight years of age, all BAMSE children were invited for clinical testing, and blood samples were obtained from 2,480 children. DNA was extracted from 2,033 samples after exclusion of samples with too little blood, lack of questionnaire data, or if parental consent to genetic analysis of the sample was not obtained. All children with a doctor's diagnosis of asthma ever (n = 251) underwent GWAS genotyping [29].

Phenotyping

Phenotypic data were collected from each participant in Costa Rica at study entry, in CAMP at randomization, and in BAMSE at one, two, four, and eight years of age. AR was defined as naso-ocular symptoms apart from colds in the past 12 months and ≥1 positive skin test reaction (STR) to allergens in Costa Rica and CAMP, and as naso-ocular symptoms in the past 12 months and ≥1 positive allergen-specific IgE (Phadiatop®, Phadia AB, Uppsala, Sweden) at eight years in BAMSE. These definitions for AR are consistent with Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 guidelines [30]. We chose not to use a physician's diagnosis to define AR given greater variability associated with this definition. We compared allergen-sensitized AR and physician-diagnosed AR in Costa Rica in a previous study [4].

Genotyping

Using data from European Americans (CEU) in the International HapMap project [31], we applied a linkage-disequilibrium (LD)-tagging algorithm (minor allele frequency ≥ 5% and r2 ≥ 0.8) to identify common variation in TSLP, OX40L, IL7R, RXRα and their 10 kb flanks. LD maps were plotted using Haploview [32]. We considered additional SNPs in TSLP to evaluate reported functional variation (rs3806933) [33] and those highlighted in previous studies of asthma (rs1837253) [34]. A total of 21 SNPs were chosen for genotyping in Costa Rican subjects and their parents using the Sequenom iPLEX platform (Sequenom, San Diego, CA) including 9 SNPs for TSLP and 4 SNPs each for OX40L, IL7R, and RXRα. We chose Costa Rica as our population for initial findings because of greater power to detect associations in this cohort relative to CAMP and BAMSE (Table 1). All power calculations were performed using Quanto v.1.2.4. (University of Southern California, Los Angeles, CA).

Genome-wide SNP genotyping for CAMP subjects and their parents was performed on Illumina Human-Hap550 Genotyping BeadChip (Illumina, Inc., San Diego, CA). Genome-wide SNP genotyping for BAMSE subjects was performed on Illumina Human 610-Quad Beadchip (Illumina, Inc., San Diego, CA). Sixteen of the CAMP GWAS SNPs and fifteen of the BAMSE GWAS SNPs overlapped with those genotyped in Costa Rican subjects and their parents. The 15 overlapping SNPs were used to replicate our initial findings (Table 2). Of these 15 SNPs, 3 were in TSLP (rs1837253, rs2289276, rs17551370), and 4 each were in OX40L (rs1234313, rs10489267, rs10489266, rs1234315), IL7R (rs1494555, rs10063294, rs2194225, rs6897932), and RXRα (rs11185647, rs12339187, rs11185659, rs10881582). The 6 SNPs that were genotyped in Costa Rica but not on both the GWAS platforms had no significant association with AR in Costa Rica. There were no differences in SNP minor allele frequencies between boys and girls in these cohorts.

In all study cohorts, duplicate genotyping was performed on approximately 5% of the sample to assess genotype reproducibility. Genotype quality control was assessed by <1% discordance rate, <5 Mendelian inconsistencies, and genotype completion rates >98% for all loci. All SNPs included in analyses were in Hardy-Weinberg equilibrium (p > 0.01).

Of the 592 Costa Rican child-parent trios genotyped, 6 were excluded from this analysis because of Mendelian inconsistencies, leaving 586 trios. Of the 422 nuclear families in CAMP trios, 25 were excluded from this analysis because of Mendelian inconsistencies (n = 6) or missing >5% of the genotypic data (n = 19), leaving 397 families. 12 children from BAMSE were excluded because of duplicate genotyping or non-European ancestry as determined by admixture mapping using principal components analysis [29], leaving 239 children for this analysis.

Statistical Analyses

We tested for association between SNPs in TSLP, OX40L, IL7R, RXRα and AR in children with asthma. Family-based association analyses were first conducted under an additive genetic model in Costa Rican families using the Pedigree-Based Association Test (PBAT) [35] implemented in Helix Tree v6.4.3 (Golden Helix, Bozeman, MT). An advantage of family-based association testing is that it is robust against population stratification and population admixture [36]. We then replicated our findings from Costa Rica in the CAMP and BAMSE cohorts. Family-based analysis using PBAT was performed in CAMP. In BAMSE, associations between SNPs and AR phenotypes were measured using the Cochran-Armitage trend test in PLINK [37]. As we have previously reported sex-specific effects for TSLP on serum total IgE [38] and asthma [11], we also performed sex-stratified analyses in all cohorts. Transmitted to undertransmitted ratios (T:U) and odds ratio estimates for AR phenotypes were obtained using PLINK [37]. To assess for joint evidence of association in the child-based cohorts, P values were combined across Costa Rica, CAMP, and BAMSE with Fisher's combined probability method [39]. Results were considered significant only when consistent associations (i.e. same allele, same direction of genetic effect) were observed in all three populations with a Fisher's combined P value of ≤ 8.0 × 10-4 (0.05/(21*3) to account for multiple testing of 21 SNPs and 3 strata (overall, male, female).

Tests for interaction between SNPs in TSLP, OX40L, IL7R, RXRα were additionally performed using PBAT given high interest in potential gene by gene interactions. Based on our power calculations using Quanto v.1.2.4 for gene by gene interactions, we recognized a priori that our power to detect such interactions would be insufficient. For example, to detect an interaction between two SNPs each with minor allele frequency 0.40 causing a change in risk of 10%, our sample size would have to be 4229 parent-child trios. We therefore limited our interaction testing to the cohort with most subjects (Costa Rica, with 592 trios) and considered this a secondary, exploratory analysis.


Results

The phenotypic characteristics of children in the Costa Rica, Childhood Asthma Management Program (CAMP), and Children, Allergy, Milieu, Stockholm, Epidemiological Survey (BAMSE) study cohorts are shown in Table 3. Consistent with the known gender distribution of asthma in childhood [40], all three cohorts had more boys than girls. Children in Costa Rica had the highest prevalence of AR.

The linkage disequilibrium (LD) patterns and minor allele frequencies (MAF) for the TSLP SNPs genotyped in all three cohorts are shown in Figure 2. There were no major differences in MAFs and LD patterns among the SNPs between the cohorts. The LD patterns and MAFs for the nine TSLP SNPs genotyped in Costa Rica are shown in Figure 3. Consistent with our LD-tagging approach, LD was generally not high between the SNPs chosen for genotyping in Costa Rica.

The results for overall and sex-stratified association testing of TSLP SNP rs1837253 and AR in Costa Rica, CAMP, and BAMSE are shown in Table 4. The association between rs1837253 and AR in all children (in analyses not stratified by sex) was significant in CAMP (P value 0.003) but not in Costa Rica or BAMSE. In sex-stratified analysis, the T allele of SNP rs1837253 was associated with reduced odds for allergen-sensitized AR in boys in all three cohorts, with P values ranging from 0.04 to 0.004. Specifically, the minor allele of rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone in all three cohorts. The combined P value across cohorts met our criteria for significance after accounting for multiple testing, with Fisher's combined P value of 1.2 × 10-4. Odds ratios (ORs) for these associations ranged from 0.56 to 0.63. In contrast to the observed results in males, female-specific associations between rs1837253 and AR were inconsistent across cohorts.

The other TSLP SNPs and SNPs in OX40L, IL7R and RXRα were not significantly associated with AR phenotypes across cohorts (Table 5).

Tests for gene by gene interactions showed twelve nominally significant interactions between SNPs in all gene pair combinations of TSLP, OX40L, RXRα and IL7R except for between RXRα and IL7R (Table 6). After accounting for 84 tests for interaction, none remained significant after correction for multiple comparisons (P value threshold for significance 0.05/84 interaction tests = 0.00060).


Discussion

This is the first study to examine genetic associations between SNPs in TSLP and AR. This is also the first study to concurrently examine associations between variants in multiple TSLP-related genes (OX40L, IL7R, RXRα) and AR. We found an inverse male-specific association between the T allele of SNP rs1837253 in TSLP and AR in three independent cohorts of children with asthma. As children with asthma are particularly vulnerable to develop and suffer morbidity from AR, our findings are of direct relevance to this population.

Our study contributes to a nascent literature on the role of TSLP in AR. Prior work on TSLP has focused on other allergic diseases [6,9-12]. That TSLP could play a role in AR is first suggested by our understanding of TSLP and its ability to drive Th2 dominant inflammation. Second, a limited number of in vitro and murine studies have reported increased TSLP expression in cell cultures and nasal epithelium from AR patients [13-16,19]. The significant association between a TSLP variant and AR that we observed across multiple large and distinct cohorts supports that TSLP plays a role in AR in humans, corroborates previous in vitro and murine studies, and supports our understanding of TSLP driving allergic inflammation.

We found male-specific associations between TSLP SNP rs1837253 and AR in children with asthma from the Costa Rica, CAMP, and BAMSE studies. This SNP was undertransmitted in boys with AR and asthma as compared to in boys with asthma alone. Although this SNP has previously been associated with asthma [11,34], the associations with AR that we found cannot be attributed to asthma alone since all subjects in our study had asthma. Our findings suggest an additional role for this SNP in the pathogenesis of AR.

Our results were more statistically significant in boys than in all children, despite reductions in power in the sex-stratified analysis. This suggests that the significant associations among males that we observed across the cohorts were not merely due to the greater number of boys in these cohorts. The gene for the TSLPR chain of the heterodimeric TSLP receptor has a sex chromosome location in humans (Xp22.3 and Yp11.3) [41], and this could partially explain a sex-specific mechanism for TSLP. Sex-dependent hormonal regulation of transcription is also possible. Sex-specific effects have been observed for TSLP [11] and for other genes [42-44].

Our study's findings are consistent with sex-specific epidemiological observations for AR. Male children become more sensitized to environmental allergens and have higher serum total IgE levels [45,46]. Nasal fluid allergen-specific IgE levels are higher in male than female patients with seasonal AR [47]. A sex-stratified analysis of inflammatory pathways using allergen-challenged CD4+ cells from AR patients showed higher expression signatures in males [47]. Sexual dimorphism has also been noted in genetic linkage and association studies of serum total IgE [38,48]. Our findings expand on previous reports of sexual dimorphism in allergic disease by identifying sex-specific effects of a genetic variant on AR.

Our laboratory previously reported a sex-specific association between rs2289276 and serum total IgE [38], and between rs1827253 and asthma [11]. rs2289276 is predicted to affect an exonic splicing enhancer, while rs1837253 is thought to disrupt a transcription factor binding site [49]. SNP rs1837253 is located 5.7 kb upstream of the TSLP transcription start site. A study by Harada et al. conducted in human bronchial epithelial suggested that a SNP in the TSLP promoter region could serve as a binding site for transcription activating protein (AP)-1, enhance AP-1 binding to regulatory elements, and lead to TSLP's downstream effects [33]. Harada et al. implicated rs3806933 as the functional SNP; they did not study rs1837253, and rs1837253 is not in LD with rs3806933 (Figure 3). We did not find an association between rs3806933 and AR, nor between rs2289276 and AR. He et al. reported associations between rs1837253 and protection from asthma, atopic asthma, and airway hyperresponsiveness [34], and Hunninghake et al. reported sex-specific associations between rs1837253 and protection from asthma in boys. These studies corroborate rs1837253 as a SNP of interest with a potential functional role.

Recognizing that TSLP interacts with other proteins to affect Th2-driven inflammation, we implemented a comprehensive approach from the outset by also examining for genetic associations between AR and SNPs in OX40L, IL7R, and RXRα. We did not observe findings that were consistent across cohorts for individual SNP associations with AR. This may have been due to unexamined gene-by-environment interactions. Shamim et al. previously reported an association between two IL7R SNPs and inhalation allergy [50]. They did not perform replication analyses in independent populations, and we did not find associations between those SNPs and AR in our cohorts. It is thought that RXRα and RXRβ can influence transcription of TSLP, but neither has been previously studied in subjects with AR [23]. The RXRα SNPs we chose to genotype capture 96% of the HapMap SNPs with MAF ≥ 10% in RXRα and its 10 kb flanks in the CEU population with r2 ≥ 0.8, so our lack of findings for RXRα was unlikely due to inadequate genotypic coverage [32]. Interestingly, our tests for gene by gene interaction among TSLP, OX40L, RXRa and IL7R in Costa Rican subjects demonstrated nominally significant results between SNPs in all gene pairs, except for between RXRα and IL7R. Lack of gene by gene interaction between RXRα and IL7R would be biologically consistent with their physically disparate roles as transcriptional regulator of TSLP and receptor for TSLP, respectively. Further gene by gene analyses with larger sample size could overcome the power limitations we faced.

Our study has additional limitations. First, our findings do not elucidate a specific mechanism. SNP rs1837253 is not in LD with other HapMap SNPs and has the potential to represent a functional SNP itself. Our work provides a specific direction for functional studies that could focus on transcriptional regulators of TSLP. Second, some of our findings in Costa Ricans may be mainly applicable to them and certain Hispanic subgroups. However, we replicated our main finding in CAMP and BAMSE, and previous findings in Costa Rica have been applicable to children of other ethnicities [51,52]. Family-based testing is also robust against population stratification and population admixture [36]. Lastly, we focused on AR in children with asthma, and it is possible that distinct associations could be found if we examined cohorts with AR only. However, our findings are relevant to a group of children at high risk for AR.


Conclusions

In summary, we found that the T allele of TSLP SNP rs1837253 was associated with reduced odds for AR in three independent cohorts of children with asthma. The association was sex-specific, as it was significant in males but not females. Our work highlights that TSLP likely plays a role in the pathogenesis of AR in children with asthma.


Competing interests

The authors declare that they have no competing interests.


Authors' contributions

SB contributed to the study design, analyzing the data, and writing the manuscript. EM contributed to analyzing the data and manuscript editing. JBW contributed to analyzing the data and manuscript editing. MG contributed to analyzing the data and manuscript editing. MS contributed to patient recruitment and manuscript editing. LA contributed to patient recruitment and manuscript editing. JLS contributed to analyzing the data and manuscript editing. GH contributed to the study design and manuscript editing. MW contributed to patient recruitment and manuscript editing. GP contributed to patient recruitment and manuscript editing. GTO contributed to patient recruitment and manuscript editing. SW contributed to patient recruitment and manuscript editing. JCC contributed to the study design, patient recruitment and writing the manuscript. All authors read and approved the final manuscript.


Acknowledgements

We thank all subjects for their participation in the Genetics of Asthma in Costa Rica, CAMP, and BAMSE studies. We acknowledge the CAMP investigators and research team, supported by NHLBI, for collection of CAMP Genetic Ancillary Study data. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham and Women's Hospital under appropriate CAMP policies and human subject's protections. This work was supported by the National Institute of Health [Grants R37 HL66289, U01 HL075419, P01 HL083069, T32 HL007427]; the Swedish Research Council; Stockholm County Council; Centre for Allergy Research, Karolinska Institutet; Swedish Heart Lung Foundation; Swedish Fulbright Commission; Riksbankens Jubileumsfond; Erik Rönnberg Scholarship; GABRIEL contract number 018996 under Integrated Program LSH-2004-1.2.5-1; the Wellcome Trust [WT084703MA].


References
Meltzer EO,Blaiss MS,Derebery MJ,Mahr TA,Gordon BR,Sheth KK,Simmons AL,Wingertzahn MA,Boyle JM,Burden of allergic rhinitis: results from the Pediatric Allergies in America surveyJ Allergy Clin ImmunolYear: 2009124S437010.1016/j.jaci.2009.05.01319592081
Thomas M,Kocevar VS,Zhang Q,Yin DD,Price D,Asthma-related health care resource use among asthmatic children with and without concomitant allergic rhinitisPediatricsYear: 200511512913415629992
Sazonov Kocevar V,Thomas J,Jonsson L,Valovirta E,Kristensen F,Yin DD,Bisgaard H,Association between allergic rhinitis and hospital resource use among asthmatic children in NorwayAllergyYear: 20056033834210.1111/j.1398-9995.2005.00712.x15679719
Bunyavanich S,Soto-Quiros ME,Avila L,Laskey D,Senter JM,Celedon JC,Risk factors for allergic rhinitis in Costa Rican children with asthmaAllergyYear: 201065225663 Epub 2009 Oct 1. 10.1111/j.1398-9995.2009.02159.x19796208
Corren J,Manning BE,Thompson SF,Hennessy S,Strom BL,Rhinitis therapy and the prevention of hospital care for asthma: a case-control studyJ Allergy Clin ImmunolYear: 200411341541910.1016/j.jaci.2003.11.03415007339
Soumelis V,Reche PA,Kanzler H,Yuan W,Edward G,Homey B,Gilliet M,Ho S,Antonenko S,Lauerma A,et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLPNat ImmunolYear: 2002367368010.1038/nrm91012055625
Allakhverdi Z,Comeau MR,Jessup HK,Yoon BR,Brewer A,Chartier S,Paquette N,Ziegler SF,Sarfati M,Delespesse G,Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cellsJ Exp MedYear: 200720425325810.1084/jem.2006221117242164
Liu YJ,TSLP in epithelial cell and dendritic cell cross talkAdv ImmunolYear: 2009101125 full_text. 19231591
Ying S,O'Connor B,Ratoff J,Meng Q,Mallett K,Cousins D,Robinson D,Zhang G,Zhao J,Lee TH,Corrigan C,Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severityJ ImmunolYear: 20051748183819015944327
Ying S,O'Connor B,Ratoff J,Meng Q,Fang C,Cousins D,Zhang G,Gu S,Gao Z,Shamji B,et al. Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary diseaseJ ImmunolYear: 20081812790279818684970
Hunninghake GM,Soto-Quiros ME,Avila L,Kim HP,Lasky-Su J,Rafaels N,Ruczinski I,Beaty TH,Mathias RA,Barnes KC,et al. TSLP polymorphisms are associated with asthma in a sex-specific fashionAllergyYear: 2010651215667510.1111/j.1398-9995.2010.02415.x20560908
Rothenberg ME,Spergel JM,Sherrill JD,Annaiah K,Martin LJ,Cianferoni A,Gober L,Kim C,Glessner J,Frackelton E,et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitisNat GenetYear: 20104228929110.1038/ng.54720208534
Mou Z,Xia J,Tan Y,Wang X,Zhang Y,Zhou B,Li H,Han D,Overexpression of thymic stromal lymphopoietin in allergic rhinitisActa OtolaryngolYear: 200815
Miyata M,Hatsushika K,Ando T,Shimokawa N,Ohnuma Y,Katoh R,Suto H,Ogawa H,Masuyama K,Nakao A,Mast cell regulation of epithelial TSLP expression plays an important role in the development of allergic rhinitisEur J ImmunolYear: 2008381487149210.1002/eji.20073780918461563
Kamekura R,Kojima T,Koizumi JI,Ogasawara N,Kurose M,Go M,Harimaya A,Murata M,Tanaka S,Chiba H,et al. Thymic stromal lymphopoietin enhances tight-junction barrier function of human nasal epithelial cellsCell Tissue ResYear: 2009338228393 Epub 2009 Sep 9. 10.1007/s00441-009-0855-119763625
Zhu DD,Zhu XW,Jiang XD,Dong Z,Thymic stromal lymphopoietin expression is increased in nasal epithelial cells of patients with mugwort pollen sensitive-seasonal allergic rhinitisChin Med J (Engl)Year: 20091222303230720079130
Ito T,Wang YH,Duramad O,Hori T,Delespesse GJ,Watanabe N,Qin FX,Yao Z,Cao W,Liu YJ,TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligandJ Exp MedYear: 20052021213122310.1084/jem.2005113516275760
Wang YH,Liu YJ,Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responsesClin Exp AllergyYear: 20093979880610.1111/j.1365-2222.2009.03241.x19400908
Seshasayee D,Lee WP,Zhou M,Shu J,Suto E,Zhang J,Diehl L,Austin CD,Meng YG,Tan M,et al. In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammationJ Clin InvestYear: 20071173868387810.1172/JCI3355918060034
Reche PA,Soumelis V,Gorman DM,Clifford T,Liu M,Travis M,Zurawski SM,Johnston J,Liu YJ,Spits H,et al. Human thymic stromal lymphopoietin preferentially stimulates myeloid cellsJ ImmunolYear: 200116733634311418668
Pandey A,Ozaki K,Baumann H,Levin SD,Puel A,Farr AG,Ziegler SF,Leonard WJ,Lodish HF,Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietinNat ImmunolYear: 20001596410881176
Park LS,Martin U,Garka K,Gliniak B,Di Santo JP,Muller W,Largaespada DA,Copeland NG,Jenkins NA,Farr AG,et al. Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: Formation of a functional heteromeric complex requires interleukin 7 receptorJ Exp MedYear: 200019265967010.1084/jem.192.5.65910974032
Li M,Messaddeq N,Teletin M,Pasquali JL,Metzger D,Chambon P,Retinoid × receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietinProc Natl Acad Sci USAYear: 2005102147951480010.1073/pnas.050738510216199515
Meltzer EO,Szwarcberg J,Pill MW,Allergic rhinitis, asthma, and rhinosinusitis: diseases of the integrated airwayJ Manag Care PharmYear: 20041031031715298529
Pearce N,Ait-Khaled N,Beasley R,Mallol J,Keil U,Mitchell E,Robertson C,Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC)ThoraxYear: 20076275876610.1136/thx.2006.07016917504817
The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Childhood Asthma Management Program Research GroupControl Clin TrialsYear: 1999209112010.1016/S0197-2456(98)00044-010027502
Himes BE,Hunninghake GM,Baurley JW,Rafaels NM,Sleiman P,Strachan DP,Wilk JB,Willis-Owen SA,Klanderman B,Lasky-Su J,et al. Genome-wide association analysis identifies PDE4D as an asthma-susceptibility geneAm J Hum GenetYear: 20098458159310.1016/j.ajhg.2009.04.00619426955
Melen E,Nyberg F,Lindgren CM,Berglind N,Zucchelli M,Nordling E,Hallberg J,Svartengren M,Morgenstern R,Kere J,et al. Interactions between glutathione S-transferase P1, tumor necrosis factor, and traffic-related air pollution for development of childhood allergic diseaseEnviron Health PerspectYear: 20081161077108410.1289/ehp.1111718709160
Moffatt M,Gut IG,Demenais F,Strachan DP,Bouzigon E,Heath S,von Mutius E,Farrall M,Lathrop M,Cookson WOCM,the GABRIEL consortiumA large-scale, consortium-based genome-wide association study of asthmaN Engl J MedYear: 20103631211122110.1056/NEJMoa090631220860503
Bousquet J,Khaltaev N,Cruz AA,Denburg J,Fokkens WJ,Togias A,Zuberbier T,Baena-Cagnani CE,Canonica GW,van Weel C,World Health Organization; GA(2)LEN; AllerGenet al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)AllergyYear: 200863816010.1111/j.1398-9995.2007.01620.x18331513
The International HapMap ProjectNatureYear: 200342678979610.1038/nature0216814685227
Barrett JC,Fry B,Maller J,Daly MJ,Haploview: analysis and visualization of LD and haplotype mapsBioinformaticsYear: 20052126326510.1093/bioinformatics/bth45715297300
Harada M,Hirota T,Jodo AI,Doi S,Kameda M,Fujita K,Miyatake A,Enomoto T,Noguchi E,Yoshihara S,et al. Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cellsAm J Respir Cell Mol BiolYear: 20094036837410.1165/rcmb.2008-0041OC18787178
He JQ,Hallstrand TS,Knight D,Chan-Yeung M,Sandford A,Tripp B,Zamar D,Bosse Y,Kozyrskyj AL,James A,et al. A thymic stromal lymphopoietin gene variant is associated with asthma and airway hyperresponsivenessJ Allergy Clin ImmunolYear: 200912422222910.1016/j.jaci.2009.04.01819539984
Lange C,DeMeo D,Silverman EK,Weiss ST,Laird NM,PBAT: tools for family-based association studiesAm J Hum GenetYear: 20047436736910.1086/38156314740322
Laird NM,Lange C,Family-based designs in the age of large-scale gene-association studiesNat Rev GenetYear: 2006738539410.1038/nrg183916619052
Purcell S,Neale B,Todd-Brown K,Thomas L,Ferreira MA,Bender D,Maller J,Sklar P,de Bakker PI,Daly MJ,Sham PC,PLINK: a tool set for whole-genome association and population-based linkage analysesAm J Hum GenetYear: 20078155957510.1086/51979517701901
Hunninghake GM,Lasky-Su J,Soto-Quiros ME,Avila L,Liang C,Lake SL,Hudson TJ,Spesny M,Fournier E,Sylvia JS,et al. Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in Costa RicansAm J Respir Crit Care MedYear: 200817783083610.1164/rccm.200711-1697OC18244952
Fisher RA,Statistical Methods for Research WorkersYear: 1932Edinburgh: Oliver and Boyd
Almqvist C,Worm M,Leynaert B,Impact of gender on asthma in childhood and adolescence: a GA2LEN reviewAllergyYear: 200863475717822448
Maglott D,Ostell J,Pruitt KD,Tatusova T,Entrez Gene: gene-centered information at NCBINucleic Acids ResYear: 200735D263110.1093/nar/gkl99317148475
Patsopoulos NA,Tatsioni A,Ioannidis JP,Claims of sex differences: an empirical assessment in genetic associationsJAMAYear: 200729888089310.1001/jama.298.8.88017712072
Raby BA,Lazarus R,Silverman EK,Lake S,Lange C,Wjst M,Weiss ST,Association of vitamin D receptor gene polymorphisms with childhood and adult asthmaAm J Respir Crit Care MedYear: 20041701057106510.1164/rccm.200404-447OC15282200
Karjalainen J,Nieminen MM,Aromaa A,Klaukka T,Hurme M,The IL-1beta genotype carries asthma susceptibility only in menJ Allergy Clin ImmunolYear: 200210951451610.1067/mai.2002.12194811898000
Guilbert TW,Morgan WJ,Zeiger RS,Bacharier LB,Boehmer SJ,Krawiec M,Larsen G,Lemanske RF,Liu A,Mauger DT,et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthmaJ Allergy Clin ImmunolYear: 20041141282128710.1016/j.jaci.2004.09.02015577824
Uekert SJ,Akan G,Evans MD,Li Z,Roberg K,Tisler C,Dasilva D,Anderson E,Gangnon R,Allen DB,et al. Sex-related differences in immune development and the expression of atopy in early childhoodJ Allergy Clin ImmunolYear: 20061181375138110.1016/j.jaci.2006.09.00817157669
Barrenas F,Andersson B,Cardell LO,Langston M,Mobini R,Perkins A,Soini J,Stahl A,Benson M,Gender differences in inflammatory proteins and pathways in seasonal allergic rhinitisCytokineYear: 20084232532910.1016/j.cyto.2008.03.00418440239
Raby BA,Soto-Quiros ME,Avila L,Lake SL,Murphy A,Liang C,Fournier E,Spesny M,Sylvia JS,Verner A,et al. Sex-specific linkage to total serum immunoglobulin E in families of children with asthma in Costa RicaHum Mol GenetYear: 20071624325310.1093/hmg/ddl44717142250
Conde L,Vaquerizas JM,Dopazo H,Arbiza L,Reumers J,Rousseau F,Schymkowitz J,Dopazo J,PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposesNucleic Acids ResYear: 200634W62162510.1093/nar/gkl07116845085
Shamim Z,Muller K,Svejgaard A,Poulsen LK,Bodtger U,Ryder LP,Association between genetic polymorphisms in the human interleukin-7 receptor alpha-chain and inhalation allergyInt J ImmunogenetYear: 20073414915110.1111/j.1744-313X.2007.00657.x17504502
Hersh CP,Raby BA,Soto-Quiros ME,Murphy AJ,Avila L,Lasky-Su J,Sylvia JS,Klanderman BJ,Lange C,Weiss ST,Celedon JC,Comprehensive testing of positionally cloned asthma genes in two populationsAm J Respir Crit Care MedYear: 200717684985710.1164/rccm.200704-592OC17702965
Hunninghake GM,Soto-Quiros ME,Avila L,Su J,Murphy A,Demeo DL,Ly NP,Liang C,Sylvia JS,Klanderman BJ,et al. Polymorphisms in IL13, total IgE, eosinophilia, and asthma exacerbations in childhoodJ Allergy Clin ImmunolYear: 2007120849010.1016/j.jaci.2007.04.03217561245

Figures

[Figure ID: F1]
Figure 1 

TSLP is a key mediator of allergic inflammation. TSLP binds to a heterodimeric receptor of TSLPR and IL7Rα chains. Its induction of Th2 mediated inflammation requires costimulation by OX40L binding to OX40. RXRα and RXRβ act as transcriptional regulators.



[Figure ID: F2]
Figure 2 

LD plot of TSLP SNPs genotyped in Costa Rica, CAMP, and BAMSE. Pairwise correlation structure for TSLP SNPs genotyped in all three cohorts.



[Figure ID: F3]
Figure 3 

LD plot of TSLP SNPs genotyped in Costa Rica. Pairwise correlation structure for TSLP SNPs genotyped in Costa Rica



Tables
[TableWrap ID: T1] Table 1 

Power calculations for genetic association studies of AR in Costa Rica, CAMP, and BAMSE


Costa Rica (n = 592) CAMP (n = 422) BAMSE (n = 239)
Allele Frequency Power to detect OR 1.5 Power to detect OR 1.3 Power to detect OR 1.5 Power to detect OR 1.3 Power to detect OR 1.5 Power to detect OR 1.3
0.10 0.89 0.52 0.77 0.40 0.23 0.12
0.20 0.99 0.75 0.94 0.61 0.36 0.18
0.30 0.997 0.85 0.98 0.71 0.44 0.22
0.40 0.998 0.88 0.98 0.76 0.48 0.24

[TableWrap ID: T2] Table 2 

SNPs analyzed in Costa Rica, CAMP, and BAMSE


SNP Gene Position Allele Allele Frequency
Costa Rica CAMP BAMSE

rs1837253 TSLP chr5:110429771 T 0.24 0.21 0.27
rs17551370 TSLP chr5:110432084 A 0.10 0.13 0.15
rs2289276 TSLP chr5:110435406 T 0.30 0.27 0.29
rs1234313 OX40L chr1:171432870 A 0.38 0.32 0.34
rs10489267 OX40L chr1:171436775 A 0.14 0.06 0.07
rs10489266 OX40L chr1:171445076 G 0.08 0.11 0.10
rs1234315 OX40L chr1:171445086 T 0.65 0.46 0.48
rs1494555 IL7R chr5:35906947 G 0.47 0.34 0.26
rs6897932 IL7R chr5:35910332 T 0.16 0.24 0.32
rs10063294 IL7R chr5:35913262 G 0.60 0.48 0.42
rs2194225 IL7R chr5:35919561 C 0.37 0.42 0.42
rs11185647 RXRα chr9:136355649 A 0.41 0.29 0.26
rs12339187 RXRα chr9:136369148 G 0.19 0.17 0.17
rs11185659 RXRα chr9:136383204 T 0.22 0.20 0.21
rs10881582 RXRα chr9:136395899 A 0.34 0.23 0.20

CAMP: Childhood Asthma Management Program

BAMSE: Children, Allergy, Milieu, Stockholm, Epidemiological Survey


[TableWrap ID: T3] Table 3 

Baseline phenotypic characteristics of children in Costa Rica, CAMP, and BAMSE


Variable Costa Rica* CAMP* BAMSE
All (n = 592) Boys (n = 351) Girls (n = 241) All (n = 422) Boys (n = 266) Girls (n = 156) All (n = 239) Boys (n = 150) Girls (n = 89)

Age-Years 9.0 (1.8) 9.1 (1.9) 8.9 (1.7) 8.7 (2.1) 8.6 (2.1) 8.9 (2.1) 8.3 (0.5) 8.3 (0.5) 8.3 (0.4)

STR or allergen-specific IgE - Any Positive 504 (85.4%) 200 (83.9%) 304 (87.1%) 370 (87.7%) 235 (88.4%) 135 (86.5%) 113 (47.3%) 78 (52%) 35 (39%)

Serum Total IgE - IU/ml 697 (867) 755 (911) 611 (792) 1095 (1920) 988 (1567) 1276 (2397) n/a n/a n/a

Nasal symptoms in past year 543 (91.7%) 334 (90.3%) 230 (93.5%) 207 (49.1%) 135 (50.8%) 72 (46.2%) 76 (31.9%) 52 (34.9%) 24 (27.0%)

Allergic Rhinitis 474 (80.1%) 282 (80.3%) 192 (79.7%) 189 (44.8%) 124 (46.6%) 65 (41.7%) 64 (26.9%) 43 (28.9%) 21 (23.6%)

Values are presented as mean (standard deviation) or number (percentage)

STR = skin test reaction

*Values are for index children in these family-based cohorts

Data not collected in BAMSE


[TableWrap ID: T4] Table 4 

Association between TSLP SNP rs1837253 minor allele T* and allergic rhinitis in Costa Rica, CAMP, and BAMSE


Costa Rica CAMP BAMSE Combined
Subjects T:U OR P value T:U OR P value OR P value Fisher's P value

All children 104:122 0.85 0.18 50:81 0.62 0.003 0.72 0.089 0.003

Boys 59:93 0.63 0.004 32:55 0.58 0.007 0.56 0.04 1.2 × 10-4

Girls^ 45:29 1.55 0.08 18:26 0.69 0.11 1.02 0.48

*Allele frequency 0.24 in Costa Rica, 0.21 in CAMP, 0.27 in BAMSE

T:U = ratio of transmitted to untransmitted alleles

^Fisher's combined P value not calculated because direction of effect inconsistent across females in these cohort.


[TableWrap ID: T5] Table 5 

Analysis of association between TSLP, RXRa, IL7R, OX40L SNPs and AR in Costa Rica, CAMP, and BAMSE


Costa Rica CAMP BAMSE



P value P value P value



SNP Gene Allele Allele Frequency All Boys Girls Allele Frequency All Boys Girls Allele Frequency All Boys Girls
rs1837253 TSLP T 0.24 0.18 0.004 0.08 0.21 0.003 0.007 0.11 0.27 0.09 0.04 0.48

rs17551370 TSLP A 0.10 0.77 0.95 0.71 0.13 0.31 0.32 0.42 0.15 0.03 0.25 0.03

rs2289276 TSLP T 0.30 0.12 0.60 0.06 0.27 0.07 0.09 0.25 0.29 0.38 0.12 0.14

rs1234313 OX40L A 0.38 0.26 0.10 0.81 0.32 0.007 0.03 0.048 0.34 0.04 0.03 0.29

rs10489267 OX40L A 0.14 0.24 0.07 0.70 0.06 0.19 0.43 0.13 0.07 0.40 0.29 0.31

rs10489266 OX40L G 0.08 0.16 0.13 0.69 0.11 0.36 0.27 0.42 0.10 0.25 0.21 0.48

rs1234315 OX40L T 0.65 0.12 0.57 0.07 0.46 0.03 0.09 0.08 0.48 0.47 0.38 0.44

rs11185647 RXRα A 0.41 0.53 0.76 0.54 0.29 0.19 0.046 0.25 0.26 0.42 0.18 0.07

rs12339187 RXRα G 0.19 0.61 0.88 0.30 0.17 0.28 0.45 0.21 0.17 0.12 0.04 0.36

rs11185659 RXRα T 0.22 0.74 0.80 0.39 0.20 0.43 0.21 0.22 0.21 0.05 0.02 0.49

rs10881582 RXRα A 0.34 0.34 0.75 0.25 0.23 0.42 0.45 0.33 0.21 0.17 0.24 0.02

rs1494555 IL7R G 0.47 0.74 0.49 0.77 0.34 0.38 0.43 0.20 0.26 0.04 0.13 0.08

rs6897932 IL7R T 0.16 0.31 0.90 0.08 0.24 0.09 0.16 0.18 0.32 0.04 0.02 0.42

rs10063294 IL7R G 0.60 0.85 0.80 0.55 0.48 0.36 0.36 0.13 0.42 0.05 0.11 0.13

rs2194225 IL7R C 0.37 0.26 0.60 0.25 0.42 0.22 0.14 0.45 0.42 0.45 0.20 0.17

[TableWrap ID: T6] Table 6 

SNP by SNP Interaction Test P values in Costa Rica


Gene TSLP TSLP TSLP OX40L OX40L OX40L OX40L RXRα RXRα RXRα RXRα IL7R IL7R IL7R IL7R
SNP rs1837253 rs17551370 rs2289276 rs1234313 rs10489267 rs10489266 rs1234315 rs11185647 rs12339187 rs11185659 rs10881582 rs1494555 rs6897932 rs10063294 rs2194225

TSLP rs1837253 NS* NS NS NS NS NS NS NS 0.00062 0.0049 0.0033 NS

TSLP rs17551370 NS NS NS NS 0.036 NS NS NS NS NS NS NS

TSLP rs2289276 NS NS 0.034 NS NS NS NS NS NS 0.016 NS NS

OX40L rs1234313 NS 0.046 0.033 0.0040 NS NS NS NS

OX40L rs10489267 0.021 NS NS NS NS 0.018 NS NS

OX40L rs10489266 NS NS NS NS NS NS NS 0.043

OX40L rs1234315 NS NS NS NS NS NS NS NS

RXRα rs11185647 NS NS NS NS

RXRα rs12339187 NS NS NS NS

RXRα rs11185659 NS NS NS NS

RXRα rs10881582 NS NS NS NS

IL7R rs1494555

IL7R rs6897932

IL7R rs10063294

IL7R rs2194225

*NS = non-significant



Article Categories:
  • Research


Previous Document:  Myocardium-derived conditioned medium improves left ventricular function in rodent acute myocardial ...
Next Document:  An integrative pharmacological approach to radio telemetry and blood sampling in pharmaceutical drug...