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:10.1371/journal.pgen.1007739

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 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

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

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 language	English (US)
Article number	e1007739
Journal	PLoS genetics
Volume	15
Issue number	4
DOIs	https://doi.org/10.1371/journal.pgen.1007739
State	Published - 2019

Funding

Brian Cade is supported by grants from the National Institutes of Health [K01-HL135405-01, R01-HL113338-04, R35-HL135818-01] and the American Thoracic Society Foundation (http:// foundation.thoracic.org). The Sleep Reading Center of Brigham and Women’s Hospital has been supported by National Institutes of Health grants [5-R01-HL046380-15 and 5-KL2-RR024990-05]. The Atherosclerosis Risk in Communities (ARIC) Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of North Carolina (N01-HC-55015, N01-HC-55018), Baylor College of Medicine (N01-HC-55016), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), and University of Mississippi Medical Center (N01-HC-55021). This Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Genotyping among the African-American cohort was supported in part by HL085251Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Framingham Heart Study is conducted and supported by NHLBI in collaboration with Boston University (Contract No. N01-HC-25195). Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL- 64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding support for the Framingham Sleep Heart Health Study was provided by NIH/NHLBI grant U01 HL 53941. The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (HHSN268201300001I / N01-HC-65233), University of Miami (HHSN268201300004I / N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I / N01-HC-65235), University of Illinois at Chicago – HHSN268201300003I / N01-HC-65236 Northwestern Univ), and San Diego State University (HHSN268201300005I / N01-HC-65237). The following Institutes/Centers/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: 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, NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at Washington University was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). The Jackson Heart Study is supported and conducted in collaboration with Jackson State University (HHSN268201300049C and HHSN268201300050C), Tougaloo College (HHSN268201300048C), and the University of Mississippi Medical Center (HHSN268201300046C and HHSN268201300047C) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). Dr. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. The authors thank the participants and data collection staff of the Jackson Heart Study. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. The Multi-Ethnic Study of Atherosclerosis (MESA) is conducted and supported by the NHLBI in collaboration with MESA investigators. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Funding support for the Sleep Polysomnography dataset was provided by grant HL56984. Provision of genotyping services supported in part by NCATS CTSI grant UL1TR000124 and NIDDK DRC grant DK063491. The Osteoporotic Fractures in Men (MrOS) Study is supported by NIH funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NCATS, and NIH Roadmap for Medical

ASJC Scopus subject areas

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

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1007739

Cite this

Cade, B. E., Chen, H., Stilp, A. M., Louie, T., Ancoli-Israel, S., Arens, R., Barfield, R., Below, J. E., Cai, J., Conomos, M. P., Evans, D. S., Frazier-Wood, A. C., Gharib, S. A., Gleason, K. J., Gottlieb, D. J., Hillman, D. R., Craig Johnson, W., Lederer, D. J., Lee, J., ... Redline, S. (2019). Associations of variants in the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep. PLoS genetics, 15(4), Article e1007739. https://doi.org/10.1371/journal.pgen.1007739

@article{59e9fbb145b640d99853edc9b2b2ffa3,

title = "Associations of variants in the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep",

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.",

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

note = "Publisher Copyright: Copyright: 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.",

year = "2019",

doi = "10.1371/journal.pgen.1007739",

language = "English (US)",

volume = "15",

journal = "PLoS genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "4",

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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, Craig Johnson, W, Lederer, DJ, Lee, J, Loredo, JS, Mei, H, Mukherjee, S, Patel, SR, Post, WS, Purcell, SM, Ramos, AR, 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, e1007739. https://doi.org/10.1371/journal.pgen.1007739

TY - JOUR

T1 - Associations of variants in the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep

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 - Craig Johnson, W.

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 R.

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

N1 - Publisher Copyright: Copyright: 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.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

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DO - 10.1371/journal.pgen.1007739

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JO - PLoS genetics

JF - PLoS genetics

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ER -

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

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