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

School of Medicine

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

6 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

ASJC Scopus subject areas

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

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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

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

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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",

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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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JO - PLoS genetics

JF - PLoS genetics

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

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