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

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

Author information

1
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, United States of America.
2
Division of Sleep Medicine, Harvard Medical School, Boston, MA, United States of America.
3
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States of America.
4
Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX United States of America.
5
Center for Precision Health, School of Public Health and School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX United States of America.
6
Department of Biostatistics, University of Washington, Seattle, WA United States of America.
7
Department of Psychiatry, University of California, San Diego, CA, United States of America.
8
The Children's Hospital at Montefiore, Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, Bronx, NY, United States of America.
9
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States of America.
10
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States of America.
11
Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States of America.
12
California Pacific Medical Center Research Institute, San Francisco, CA, United States of America.
13
USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, United States of America.
14
Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle WA, United States of America.
15
Department of Public Health Sciences, University of Chicago, Chicago, IL, United States of America.
16
VA Boston Healthcare System, Boston, MA, United States of America.
17
Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
18
Departments of Medicine and Epidemiology, Columbia University, New York, NY, United States of America.
19
Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, UC San Diego School of Medicine, La Jolla, CA, United States of America.
20
Department of Data Science, University of Mississippi Medical Center, Jackson, MS, United States of America.
21
Sleep Health Service, Respiratory and Sleep Services, Southern Adelaide Local Health Network, Adelaide, South Australia.
22
Adelaide Institute for Sleep Health, Flinders University, Adelaide, South Australia.
23
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America.
24
Division of Cardiology, Johns Hopkins University, Baltimore, MD, United States of America.
25
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States of America.
26
Department of Neurology, Center for Circadian and Sleep Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America.
27
Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
28
The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, United States of America.
29
Department of Psychiatry, Neurology, and Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, United States of America.
30
San Francisco VA Medical Center, San Francisco, CA, United States of America.
31
School of Public Health, University of Adelaide, South Australia, Australia.
32
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson MS, United States of America.
33
Division of Genetics, Brigham and Women's Hospital, Boston, MA, United States of America.
34
Division of Medical Sciences, Harvard Medical School, Boston, MA, United States of America.
35
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States of America.
36
Center for Genomic Medicine and Department of Anesthesia, Pain, and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, United States of America.
37
Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States of America.

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.

PMID:
30990817
PMCID:
PMC6467367
DOI:
10.1371/journal.pgen.1007739
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors have declared that no competing interests exist.

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