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

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

27 Citations (Scopus)

58 Downloads (Pure)

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 SpO ₂ (rs78136548 p = 2.70 × 10 ⁻¹⁰). SNPs at 10q22 were associated with all three traits including average SpO ₂ (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
Article number	e1007739
Number of pages	31
Journal	PloS Genetics
Volume	15
Issue number	4
DOIs	https://doi.org/10.1371/journal.pgen.1007739
Publication status	Published - 1 Apr 2019

Bibliographical note

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.

Keywords

Sleep apnea
Oxyhaemoglobin
Interleukin 18

UN SDGs

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

Access to Document

10.1371/journal.pgen.1007739Licence: CC0

Cade_Associations_P2019Final published version, 1.51 MBLicence: CC0

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., Johnson, W. C., 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{2b2d30afe1f2429d85f1bbeca856e354,

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 SpO 2 (rs78136548 p = 2.70 × 10 −10). SNPs at 10q22 were associated with all three traits including average SpO 2 (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. ",

keywords = "Sleep apnea, Oxyhaemoglobin, Interleukin 18",

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 Johnson, {W. Craig} 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 = "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",

month = apr,

day = "1",

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

language = "English",

volume = "15",

journal = "PloS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "4",

}

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, 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 - 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 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 - 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 - 2019/4/1

Y1 - 2019/4/1

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 SpO 2 (rs78136548 p = 2.70 × 10 −10). SNPs at 10q22 were associated with all three traits including average SpO 2 (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 SpO 2 (rs78136548 p = 2.70 × 10 −10). SNPs at 10q22 were associated with all three traits including average SpO 2 (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.

KW - Sleep apnea

KW - Oxyhaemoglobin

KW - Interleukin 18

UR - http://www.scopus.com/inward/record.url?scp=85064969866&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1007739

DO - 10.1371/journal.pgen.1007739

M3 - Article

C2 - 30990817

AN - SCOPUS:85064969866

SN - 1553-7390

VL - 15

JO - PloS Genetics

JF - PloS Genetics

IS - 4

M1 - e1007739

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this