Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep

PLoS Genet. 2019 Apr 16;15(4):e1007739. doi: 10.1371/journal.pgen.1007739. eCollection 2019 Apr.


Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Adhesion Molecules, Neuronal / genetics
  • Computational Biology
  • Extracellular Matrix Proteins / genetics
  • Female
  • Gene Regulatory Networks
  • Genetic Variation
  • Genome-Wide Association Study
  • Hexokinase / genetics*
  • Humans
  • Hypoxia / blood
  • Hypoxia / genetics
  • Interleukin-18 Receptor alpha Subunit / genetics*
  • Male
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • Nerve Tissue Proteins / genetics
  • Oxygen / blood
  • Oxyhemoglobins / metabolism*
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Serine Endopeptidases / genetics
  • Sleep / genetics*
  • Sleep Apnea Syndromes / blood
  • Sleep Apnea Syndromes / genetics
  • Young Adult


  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • IL18R1 protein, human
  • Interleukin-18 Receptor alpha Subunit
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nerve Tissue Proteins
  • Oxyhemoglobins
  • HK1 protein, human
  • Hexokinase
  • Serine Endopeptidases
  • reelin protein
  • Oxygen

Grant support