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Role of inducible nitric oxide synthase in asthma risk and lung function growth during adolescence
  1. Talat Islam1,
  2. Carrie Breton1,
  3. Muhammad T Salam1,
  4. Rob McConnell1,
  5. Made Wenten1,
  6. W James Gauderman1,
  7. David Conti1,
  8. David Van Den Berg2,
  9. John M Peters1,
  10. Frank D Gilliland1
  1. 1Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  2. 2Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  1. Correspondence to Professor Talat Islam, Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, 1540 Alcazar Street, CHP 236, Los Angeles, CA 90033, USA; islam{at}usc.edu.

Abstract

Background Inducible nitric oxide (NO) synthase (iNOS, encoded by NOS2A) produces NO in response to environmental stimuli, which can result in nitrosative stress. Because nitrosative stress affects respiratory health, it was hypothesised that variants in NOS2A are associated with asthma incidence and lung function growth during adolescence.

Methods In this prospective study, spirometric testing was performed at school and a presence or absence of asthma was ascertained annually by questionnaire among children participating in the Southern California Children's Health Study. 24 single nucleotide polymorphisms (SNPs) of the NOS2A region (with seven promoter SNPs in one haplotype block), spanning 20 kb upstream and 10 kb downstream were genotyped. Association between the NOS2A region and asthma or lung function growth was tested using genetic block-specific principal component and haplotype analyses. This study was restricted to children with Latino and Caucasian ancestry for analyses of both asthma (n=1596) and lung function growth (n=2108).

Result A pair of “yin–yang” haplotypes in the promoter region showed strong association with new-onset asthma and lung function growth. The “yin” haplotype (h0111101) was associated with 44% increased asthma risk (p=0.003) and reduced forced expiratory volume in 1 s (FEV1) growth from 10 to 18 years of age (−29.46 ml, p=0.07), whereas the “yang”(h1000010) haplotype was associated with 23% reduced asthma risk (p=0.13) and better FEV1 growth (43.84 ml, p=0.01). Furthermore, the increased asthma risk associated with h0111101 was restricted to children with the GSTM1 “null” genotype (interaction p=0.002, HR 1.89, 95% CI 1.34 to 2.60).

Conclusion Common haplotypes in the NOS2A promoter are associated with new-onset asthma and lung function growth. These effects are stronger in adolescents with the GSTM1 “null” genotype.

  • NOS2A
  • GSTM1
  • asthma and lung function
  • asthma genetics
  • oxidative stress
  • respiratory measurement
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Footnotes

  • Supplementary materials and tables are published online only at http://thx.bmj.com/content/vol65/issue2

  • Funding This work was supported by the Southern California Environmental Health Sciences Center (grant # 5P30ES007048) funded by the National Institute of Environmental Health Sciences; the Children's Environmental Health Center (grant #s 5P01ES009581, R826708-01 and RD831861-01) funded by the National Institute of Environmental Health Sciences and the Environmental Protection Agency; the National Institute of Environmental Health Sciences (grant # 5P01ES011627); the National Heart, Lung and Blood Institute (grant #s 5R01HL061768 and 5R01HL076647); and the Hastings Foundation. Other funders: NIH.

  • Competing interests None.

  • Ethics This study was conducted with the approval of the University of Southern California IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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