PLoS Genetics (Apr 2019)

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

  • Brian E Cade,
  • Han Chen,
  • Adrienne M Stilp,
  • Tin Louie,
  • Sonia Ancoli-Israel,
  • Raanan Arens,
  • Richard Barfield,
  • Jennifer E Below,
  • Jianwen Cai,
  • Matthew P Conomos,
  • Daniel S Evans,
  • Alexis C Frazier-Wood,
  • Sina A Gharib,
  • Kevin J Gleason,
  • Daniel J Gottlieb,
  • David R Hillman,
  • W Craig Johnson,
  • David J Lederer,
  • Jiwon Lee,
  • Jose S Loredo,
  • Hao Mei,
  • Sutapa Mukherjee,
  • Sanjay R Patel,
  • Wendy S Post,
  • Shaun M Purcell,
  • Alberto R Ramos,
  • Kathryn J Reid,
  • Ken Rice,
  • Neomi A Shah,
  • Tamar Sofer,
  • Kent D Taylor,
  • Timothy A Thornton,
  • Heming Wang,
  • Kristine Yaffe,
  • Phyllis C Zee,
  • Craig L Hanis,
  • Lyle J Palmer,
  • Jerome I Rotter,
  • Katie L Stone,
  • Gregory J Tranah,
  • James G Wilson,
  • Shamil R Sunyaev,
  • Cathy C Laurie,
  • Xiaofeng Zhu,
  • Richa Saxena,
  • Xihong Lin,
  • Susan Redline

DOI
https://doi.org/10.1371/journal.pgen.1007739
Journal volume & issue
Vol. 15, no. 4
p. e1007739

Abstract

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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.