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. LoredoHao Mei, Sutapa Mukherjee, Sanjay R. Patel, Wendy S. Post, Shaun M. Purcell, Alberto 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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)e1007739
JournalPLoS genetics
Volume15
Issue number4
DOIs
StatePublished - Apr 1 2019

Fingerprint

Interleukin-18 Receptor alpha Subunit
interleukin-18
Oxyhemoglobins
Hexokinase
hexokinase
sleep
Sleep
saturation
Single Nucleotide Polymorphism
receptors
Sleep Apnea Syndromes
hypoxia
breathing
Genome
Inflammasomes
genome
Comorbidity
oxygenation
genetic background
Phenotype

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Cade, B. E., Chen, H., Stilp, A. M., Louie, T., Ancoli-Israel, S., Arens, R., ... Redline, S. (2019). Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep. PLoS genetics, 15(4), e1007739. https://doi.org/10.1371/journal.pgen.1007739

Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep. / Cade, Brian E.; Chen, Han; Stilp, Adrienne M.; Louie, Tin; Ancoli-Israel, Sonia; Arens, Raanan; Barfield, Richard; Below, Jennifer E.; Cai, Jianwen; Conomos, Matthew P.; Evans, Daniel S.; Frazier-Wood, Alexis C.; Gharib, Sina A.; Gleason, Kevin J.; Gottlieb, Daniel J.; Hillman, David R.; Johnson, W. Craig; Lederer, David J.; Lee, Jiwon; Loredo, Jose S.; Mei, Hao; Mukherjee, Sutapa; Patel, Sanjay R.; Post, Wendy S.; Purcell, Shaun M.; Ramos, Alberto; Reid, Kathryn J.; Rice, Ken; Shah, Neomi A.; Sofer, Tamar; Taylor, Kent D.; Thornton, Timothy A.; Wang, Heming; Yaffe, Kristine; Zee, Phyllis C.; Hanis, Craig L.; Palmer, Lyle J.; Rotter, Jerome I.; Stone, Katie L.; Tranah, Gregory J.; Wilson, James G.; Sunyaev, Shamil R.; Laurie, Cathy C.; Zhu, Xiaofeng; Saxena, Richa; Lin, Xihong; Redline, Susan.

In: PLoS genetics, Vol. 15, No. 4, 01.04.2019, p. e1007739.

Research output: Contribution to journalArticle

Cade, BE, Chen, H, Stilp, AM, Louie, T, Ancoli-Israel, S, Arens, R, Barfield, R, Below, JE, Cai, J, Conomos, MP, Evans, DS, Frazier-Wood, AC, Gharib, SA, Gleason, KJ, Gottlieb, DJ, Hillman, DR, Johnson, WC, Lederer, DJ, Lee, J, Loredo, JS, Mei, H, Mukherjee, S, Patel, SR, Post, WS, Purcell, SM, Ramos, A, Reid, KJ, Rice, K, Shah, NA, Sofer, T, Taylor, KD, Thornton, TA, Wang, H, Yaffe, K, Zee, PC, Hanis, CL, Palmer, LJ, Rotter, JI, Stone, KL, Tranah, GJ, Wilson, JG, Sunyaev, SR, Laurie, CC, Zhu, X, Saxena, R, Lin, X & Redline, S 2019, 'Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep', PLoS genetics, vol. 15, no. 4, pp. e1007739. https://doi.org/10.1371/journal.pgen.1007739
Cade, Brian E. ; Chen, Han ; Stilp, Adrienne M. ; Louie, Tin ; Ancoli-Israel, Sonia ; Arens, Raanan ; Barfield, Richard ; Below, Jennifer E. ; Cai, Jianwen ; Conomos, Matthew P. ; Evans, Daniel S. ; Frazier-Wood, Alexis C. ; Gharib, Sina A. ; Gleason, Kevin J. ; Gottlieb, Daniel J. ; Hillman, David R. ; Johnson, W. Craig ; Lederer, David J. ; Lee, Jiwon ; Loredo, Jose S. ; Mei, Hao ; Mukherjee, Sutapa ; Patel, Sanjay R. ; Post, Wendy S. ; Purcell, Shaun M. ; Ramos, Alberto ; Reid, Kathryn J. ; Rice, Ken ; Shah, Neomi A. ; Sofer, Tamar ; Taylor, Kent D. ; Thornton, Timothy A. ; Wang, Heming ; Yaffe, Kristine ; Zee, Phyllis C. ; Hanis, Craig L. ; Palmer, Lyle J. ; Rotter, Jerome I. ; Stone, Katie L. ; Tranah, Gregory J. ; Wilson, James G. ; Sunyaev, Shamil R. ; Laurie, Cathy C. ; Zhu, Xiaofeng ; Saxena, Richa ; Lin, Xihong ; Redline, Susan. / Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep. In: PLoS genetics. 2019 ; Vol. 15, No. 4. pp. e1007739.
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AU - Cade, Brian E.

AU - Chen, Han

AU - Stilp, Adrienne M.

AU - Louie, Tin

AU - Ancoli-Israel, Sonia

AU - Arens, Raanan

AU - Barfield, Richard

AU - Below, Jennifer E.

AU - Cai, Jianwen

AU - Conomos, Matthew P.

AU - Evans, Daniel S.

AU - Frazier-Wood, Alexis C.

AU - Gharib, Sina A.

AU - Gleason, Kevin J.

AU - Gottlieb, Daniel J.

AU - Hillman, David R.

AU - Johnson, W. Craig

AU - Lederer, David J.

AU - Lee, Jiwon

AU - Loredo, Jose S.

AU - Mei, Hao

AU - Mukherjee, Sutapa

AU - Patel, Sanjay R.

AU - Post, Wendy S.

AU - Purcell, Shaun M.

AU - Ramos, Alberto

AU - Reid, Kathryn J.

AU - Rice, Ken

AU - Shah, Neomi A.

AU - Sofer, Tamar

AU - Taylor, Kent D.

AU - Thornton, Timothy A.

AU - Wang, Heming

AU - Yaffe, Kristine

AU - Zee, Phyllis C.

AU - Hanis, Craig L.

AU - Palmer, Lyle J.

AU - Rotter, Jerome I.

AU - Stone, Katie L.

AU - Tranah, Gregory J.

AU - Wilson, James G.

AU - Sunyaev, Shamil R.

AU - Laurie, Cathy C.

AU - Zhu, Xiaofeng

AU - Saxena, Richa

AU - Lin, Xihong

AU - Redline, Susan

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