Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy

Pediatr Res. 2015 Mar;77(3):472-6. doi: 10.1038/pr.2014.206. Epub 2014 Dec 18.


Background: In recent years, increasing numbers of preterm infants have been exposed to inhaled nitric oxide (iNO). This population has decreased methemoglobin (MetHb) reductase activity in their erythrocytes, which may increase the risk of MetHb toxicity. We sought to determine if genetic factors are associated with the observed variance in MetHb levels.

Methods: A population of 127 preterm infants was genotyped for five single-nucleotide polymorphisms (SNPs) in the CYB5A and CYB5R3 genes. iNO dose and levels of MetHb were obtained by chart abstraction. ANOVA was performed to identify genetic associations with MetHb levels.

Results: An association was found between the heterozygous genotype (GA) of rs916321 in the CYB5R3 gene and the mean of the first recorded MetHb levels in Caucasian infants (P = 0.01). This result remained significant after adjustment for the iNO dose (P = 0.009), gender (P = 0.03), multiple gestation (P = 0.03), birth weight (P = 0.02), and gestational age (P = 0.02). No significant associations were found with the other SNPs.

Conclusion: We demonstrate a novel genetic association with neonatal MetHb levels. Identification of genetic risk factors may be useful in determining which preterm infants are most at risk of developing MetHb toxicity with the use of iNO.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Cytochrome-B(5) Reductase / genetics*
  • Cytochrome-B(5) Reductase / metabolism
  • Cytochromes b5 / genetics
  • Erythrocytes / drug effects
  • Humans
  • Infant, Newborn
  • Infant, Premature
  • Methemoglobin / metabolism*
  • Nitric Oxide / administration & dosage
  • Nitric Oxide / pharmacology*
  • Polymorphism, Single Nucleotide / genetics


  • CYB5A protein, human
  • Nitric Oxide
  • Methemoglobin
  • Cytochromes b5
  • CYB5R3 protein, human
  • Cytochrome-B(5) Reductase