Liza Bronner Murrison1, Xiaomeng Ren2, Kristina Preusse3, Hua He4, John Kroner2, Xiaoting Chen5, Seth Jenkins2, Elisabet Johansson2, Jocelyn M Biagini1, Matthew T Weirauch6, Raphael Kopan7, Lisa J Martin8, Gurjit K Khurana Hershey9. 1. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 2. Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 3. Division of Development Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 4. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 5. Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 6. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 7. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Development Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 8. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 9. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: gurjit.hershey@cchmc.org.
Abstract
BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine important in initiation of allergic inflammation. Single nucleotide polymorphisms (SNPs) in TSLP are associated with asthma, yet studies have shown inconsistent associations between circulating TSLP and asthma. Studies that integrate the combined effects of TSLP genotype, TSLP mRNA, circulating TSLP levels, and asthma outcome are lacking. OBJECTIVES: This study sought to recruit a novel cohort based on asthma-relevant TSLP SNPs and determine their impact on TSLP mRNA expression and TSLP circulating protein levels, and their individual and combined effects on asthma. METHODS: This study developed an algorithm to prioritize TSLP SNPs and recruited 51 carriers and noncarriers based on TSLP genotypes. TSLP mRNA was quantified in nasal epithelial cells and circulating TSLP levels in plasma. This study determined the associations of defined TSLP risk genotypes and/or TSLP mRNA and protein levels with asthma. RESULTS: TSLP mRNA expression, but not circulating TSLP, was significantly increased in people who are asthmatic compared with in people who are nonasthmatic (P = .007; odds ratio, 1.44). Notably, 90% of children with the defined TSLP risk genotypes and high nasal TSLP mRNA expression (top tertile) had asthma compared with 40% of subjects without risk genotypes and with low TSLP expression (bottom tertile) (P = .024). No association between circulating TSLP and asthma was observed. CONCLUSIONS: Collectively, these data suggest childhood asthma is modified by the combined effects of TSLP genotype and TSLP expression in the nasal epithelium. The increased asthma risk likely manifests when genetic variation enables expression quantitative trait loci in the TSLP locus to elevate TSLP. It is important to consider both biomarkers when factoring asthma risk.
BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine important in initiation of allergic inflammation. Single nucleotide polymorphisms (SNPs) in TSLP are associated with asthma, yet studies have shown inconsistent associations between circulating TSLP and asthma. Studies that integrate the combined effects of TSLP genotype, TSLP mRNA, circulating TSLP levels, and asthma outcome are lacking. OBJECTIVES: This study sought to recruit a novel cohort based on asthma-relevant TSLP SNPs and determine their impact on TSLP mRNA expression and TSLP circulating protein levels, and their individual and combined effects on asthma. METHODS: This study developed an algorithm to prioritize TSLP SNPs and recruited 51 carriers and noncarriers based on TSLP genotypes. TSLP mRNA was quantified in nasal epithelial cells and circulating TSLP levels in plasma. This study determined the associations of defined TSLP risk genotypes and/or TSLP mRNA and protein levels with asthma. RESULTS: TSLP mRNA expression, but not circulating TSLP, was significantly increased in people who are asthmatic compared with in people who are nonasthmatic (P = .007; odds ratio, 1.44). Notably, 90% of children with the defined TSLP risk genotypes and high nasal TSLP mRNA expression (top tertile) had asthma compared with 40% of subjects without risk genotypes and with low TSLP expression (bottom tertile) (P = .024). No association between circulating TSLP and asthma was observed. CONCLUSIONS: Collectively, these data suggest childhood asthma is modified by the combined effects of TSLP genotype and TSLP expression in the nasal epithelium. The increased asthma risk likely manifests when genetic variation enables expression quantitative trait loci in the TSLP locus to elevate TSLP. It is important to consider both biomarkers when factoring asthma risk.
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