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.
2019
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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.

Details

Title
Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep
Author
Cade, Brian E. : Harvard University : (http://orcid.org/0000-0003-1424-0673)
Chen, Han : University of Texas Health Science Center at Houston : (http://orcid.org/0000-0002-9510-4923)
Stilp, Adrienne M. : University of Washington
Louie, Tin : University of Washington
Ancoli-Israel, Sonia : University of California San Diego
Arens, Raanan : Albert Einstein College of Medicine
Barfield, Richard : Harvard University : (http://orcid.org/0000-0002-6276-7704)
Below, Jennifer E. : Vanderbilt University
Cai, Jianwen : University of North Carolina at Chapel Hill
Conomos, Matthew P. : University of Washington
Evans, Daniel S. : California Pacific Medical Center Research Institute
Frazier-Wood, Alexis C. : Baylor College of Medicine
Gharib, Sina A. : University of Washington
Gleason, Kevin J. : University of Chicago
Gottlieb, Daniel J. : Brigham and Women's Hospital : (http://orcid.org/0000-0001-8812-8751)
Hillman, David R. : Sir Charles Gairdner Hospital
Johnson, W. Craig : University of Washington
Lederer, David J. : Columbia University : (http://orcid.org/0000-0001-5258-0228)
Lee, Jiwon : Brigham and Women's Hospital : (http://orcid.org/0000-0002-4079-7494)
Loredo, Jose S. : University of California San Diego
Content Type
Article
Published in
PLOS Genetics
Identifier(s)
DOI: https://doi.org/10.1371/journal.pgen.1007739
Data availability statement

Full meta-analysis results are freely available from http://www.sleepdisordergenetics.org/informational/data

Funding Information
National Institutes of Health, K01-HL135405-01
National Institutes of Health, R01-HL113338-04
National Institutes of Health, R35-HL135818-01
American Thoracic Society Foundation
National Institutes of Health, 5-R01-HL046380-15
National Institutes of Health, 5-KL2-RR024990-05
National Heart, Lung, and Blood Institute, N01-HC-55015
National Heart, Lung, and Blood Institute, N01-HC-55018
National Heart, Lung, and Blood Institute, N01-HC-55016
National Heart, Lung, and Blood Institute, N01-HC-55019
National Heart, Lung, and Blood Institute, N01-HC-55020
National Heart, Lung, and Blood Institute, N01-HC-55021
National Heart, Lung, and Blood Institute, HHSN268201200036C
National Heart, Lung, and Blood Institute, HHSN268200800007C
National Heart, Lung, and Blood Institute, N01HC55222
National Heart, Lung, and Blood Institute, N01HC85079
National Heart, Lung, and Blood Institute, N01HC85080
National Heart, Lung, and Blood Institute, N01HC85081
National Heart, Lung, and Blood Institute, N01HC85082
National Heart, Lung, and Blood Institute, N01HC85083
National Heart, Lung, and Blood Institute, N01HC85086
National Heart, Lung, and Blood Institute, U01HL080295
National Heart, Lung, and Blood Institute, R01HL087652
National Heart, Lung, and Blood Institute, R01HL105756
National Heart, Lung, and Blood Institute, R01HL103612
National Heart, Lung, and Blood Institute, R01HL120393
National Heart, Lung, and Blood Institute, R01HL130114
National Institute of Neurological Disorders and Stroke, HL085251
National Institute on Aging, R01AG023629
National Center for Advancing Translational Sciences
CTSI , UL1TR000124
National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center, DK063491
National Heart, Lung, and Blood Institute, N01-HC-25195
National Heart, Lung, and Blood Institute, N02-HL- 64278
National Heart, Lung, and Blood Institute, U01 HL 53941
National Heart, Lung, and Blood Institute, HHSN268201300001I / N01-HC-65233
National Heart, Lung, and Blood Institute, HHSN268201300004I / N01-HC-65234
National Heart, Lung, and Blood Institute, HHSN268201300002I / N01-HC-65235
National Heart, Lung, and Blood Institute, HHSN268201300003I / N01-HC-65236
National Heart, Lung, and Blood Institute, HHSN268201300005I / N01-HC-65237
National Institute on Minority Health and Health Disparities
National Institute on Deafness and Other Communication Disorders
National Institute of Dental and Craniofacial Research
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Neurological Disorders and Stroke
National Heart, Lung, and Blood Institute, HHSN268201300005C AM03
National Heart, Lung, and Blood Institute, HHSN268201300005C MOD03
National Heart, Lung, and Blood Institute, HHSN268201300049C
National Heart, Lung, and Blood Institute, HHSN268201300050C
National Heart, Lung, and Blood Institute, HHSN268201300048C
National Heart, Lung, and Blood Institute, HHSN268201300046C
National Heart, Lung, and Blood Institute, HHSN268201300047C
National Institute of General Medical Sciences., U54GM115428
National Heart, Lung, and Blood Institute, HHSN268201500003I
National Heart, Lung, and Blood Institute, N01-HC-95159
National Heart, Lung, and Blood Institute, N01-HC-95160
National Heart, Lung, and Blood Institute, N01-HC-95161
National Heart, Lung, and Blood Institute, N01-HC-95162
National Heart, Lung, and Blood Institute, N01-HC-95163
National Heart, Lung, and Blood Institute, N01-HC-95164
National Heart, Lung, and Blood Institute, N01-HC-95165
National Heart, Lung, and Blood Institute, N01-HC-95166
National Heart, Lung, and Blood Institute, N01-HC-95167
National Heart, Lung, and Blood Institute, N01-HC-95168
National Heart, Lung, and Blood Institute, N01-HC-95169
National Heart, Lung, and Blood Institute, UL1-TR-000040
National Heart, Lung, and Blood Institute, UL1-TR-001079
National Heart, Lung, and Blood Institute, UL1-TR-001420
National Heart, Lung, and Blood Institute, UL1-TR-001881
National Heart, Lung, and Blood Institute, DK063491
National Heart, Lung, and Blood Institute, N02-HL-64278
HL56984
NCATS CTSI, UL1TR000124
NIDDK DRC, DK063491
National Institute on Aging
NIA NIAMS, U01 AG027810
NIA NIAMS, U01 AG042124
NIA NIAMS, U01 AG042139
NIA NIAMS, U01 AG042140
NIA NIAMS, U01 AG042143
NIA NIAMS, U01 AG042145
NIA NIAMS, U01 AG042168
NIA NIAMS, U01 AR066160
NIA NIAMS, UL1 TR000128
National Heart, Lung, and Blood Institute, R01 HL071194
National Heart, Lung, and Blood Institute, R01 HL070848
National Heart, Lung, and Blood Institute, R01 HL070847
National Heart, Lung, and Blood Institute, R01 HL070842
National Heart, Lung, and Blood Institute, R01 HL070841
National Heart, Lung, and Blood Institute, R01 HL070837
National Heart, Lung, and Blood Institute, R01 HL070838
National Heart, Lung, and Blood Institute, R01 HL070839
NIAMS, RC2 AR058973
National Institutes of Health, R01 DK073541
National Institutes of Health, U01 DK085501
National Institutes of Health, R01 AI085014
National Institutes of Health, R01 HL102830
Sir Charles Gairdner and Hollywood Private Hospital Research Foundations
University of Texas Health Science Center at Houston
Western Australian Sleep Disorders Research Institute
University of Western Australia
Ontario Institute for Cancer Research
University of Toronto, McLaughlin Centre Accelerator Grant
Publication Date
2019-04-16
Language
English
Copyright Statement

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Record Appears in
Biological Sciences Division > Public Health Sciences
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Record Created
2023-06-07

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