Functional variants in the thromboxane A2 receptor gene are associated with lung function in childhood-onset asthma

K. Takeuchi, Y. Mashimo, N. Shimojo, T. Arima, Y. Inoue, Y. Morita, K. Sato, S. Suzuki, T. Nishimuta, H. Watanabe, A. Hoshioka, M. Tomiita, A. Yamaide, M. Watanabe, Y. Okamoto, Y. Kohno, A. Hata, Y. Suzuki

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Background: The thromboxane A2 receptor (TBXA2R) gene is associated with asthma, but no functional genetic variations are known to associate with the disease or its related phenotypes. Objective: To investigate the association of TBXA2R polymorphisms with asthma susceptibility and related phenotypes and to identify functionally relevant polymorphisms. Methods: We performed comprehensive sequencing of the TBXA2R gene in 48 Japanese control subjects and found a set of variants (SNP1 G>T rs2238634, SNP2 T>G rs2238633, SNP3 C>T rs2238632 and SNP4 G>A rs2238631) in intron 1 in linkage disequilibrium with c.795 T>C rs1131882, which was previously reported to be associated with asthma and related phenotypes. To investigate the effect of four common haplotypes (H1, H2, H3 and H4) on transcriptional activity, we performed a luciferase assay in primary bronchial smooth muscle cells (BSMCs) and human airway epithelial cells (BEAS-2B). We also studied the haplotype association with lung function, TBXA2R mRNA levels, and eosinophil fraction/count in peripheral blood in childhood-onset asthma patients and/or controls. Results: H2 and H4, containing minor alleles of SNP2 and SNP3, had significantly higher transcriptional activities than H1 consisting of major alleles (P < 0.001 in BSMCs and BEAS-2B). Homozygotes for redefined haplotype h2 corresponding to minor alleles of SNP2 and SNP3 were associated with lower lung function in childhood-onset asthma patients compared to other zygotes (baseline Forced expiratory volume in one second (FEV1)/ Forced vital capacity (FVC) and Forced expiratory flow between 25% and 75% of the FVC (%FEF25-75%): P = 0.00201 and 0.0128, respectively, and post-bronchodilator FEV1/FVC and %FEF25-75%: P = 0.00224 and 0.0393 respectively). Haplotype h2 was also associated with higher mRNA levels in control peripheral blood cells and higher blood eosinophil fractions and counts in female controls. Conclusions and Clinical Relevance: Genetic variants were identified in the TBXA2R gene that influenced transcriptional activity and were associated with asthma-related phenotypes. Thromboxane pathways may therefore play important roles in airway inflammation and remodelling in asthma patients.

Original languageEnglish
Pages (from-to)413-424
Number of pages12
JournalClinical and Experimental Allergy
Volume43
Issue number4
DOIs
Publication statusPublished - 2013 Apr

Keywords

  • Childhood-onset asthma
  • Eosinophil
  • Haplotype
  • Lung function
  • Single nucleotide polymorphism
  • Thromboxane A2 receptor gene

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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