Genetic variants in inducible nitric oxide synthase gene are associated with the risk of radiation-induced lung injury in lung cancer patients receiving definitive thoracic radiation

Radiother Oncol. 2014 May;111(2):194-8. doi: 10.1016/j.radonc.2014.03.001. Epub 2014 Apr 17.


Background and purpose: Nitric oxide (NO), mainly synthesized by inducible nitric oxide synthase (NOS2) in pathological conditions, plays an important role in cytotoxicity, inflammation and fibrosis. Elevations in exhaled NO after thoracic radiation have been reported to predict radiation-induced lung injury (RILI). This study examined whether genetic variations in NOS2 gene is associated with the risk of RILI.

Material and methods: A cohort of 301 patients between 2009 and 2011 were genotyped for 21 single nucleotide polymorphisms (SNPs) in the NOS2 gene by the Sequenom MassArray system. Kaplan-Meier cumulative probability was used to assess RILI risk and Cox proportional hazards analyses were performed to evaluate the effect of NOS2 genotypes on RILI.

Results: Multivariate analysis found that three SNPs (rs2297518, rs1137933 and rs16949) in NOS2 were significantly associated with risk of RILI⩾2 (P value=0.001, 0.000092, 0.001, respectively) after adjusting for other covariates. Their associations were independent of radiation dose and mean lung dose. Further haplotype analysis indicated that the ATC haplotype of three SNPs is associated with reducing the risk of developing RILI.

Conclusion: Our results demonstrate that genetic variants of NOS2 may serve as a reliable predictor of RILI in lung cancer patients treated with thoracic radiation.

Keywords: Inducible nitric oxide synthase; Lung cancer; Radiation-induced lung injury; Radiotherapy; Single nucleotide polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genetic Variation
  • Haplotypes*
  • Humans
  • Kaplan-Meier Estimate
  • Lung / radiation effects*
  • Lung Injury / etiology*
  • Lung Injury / genetics
  • Lung Neoplasms / radiotherapy*
  • Male
  • Middle Aged
  • Nitric Oxide Synthase Type II / genetics*
  • Polymorphism, Single Nucleotide
  • Proportional Hazards Models
  • Radiation Injuries / genetics*
  • Radiotherapy, Intensity-Modulated / adverse effects


  • NOS2 protein, human
  • Nitric Oxide Synthase Type II