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

被引：25

作者：

Cade, Brian E. ^{[1
,2
,3
]}

Chen, Han ^{[4
,5
,6
]}

Stilp, Adrienne M. ^{[7
]}

Louie, Tin ^{[7
]}

Ancoli-Israel, Sonia ^{[8
]}

Arens, Raanan ^{[9
]}

Barfield, Richard ^{[10
]}

Below, Jennifer E. ^{[11
]}

Cai, Jianwen ^{[12
]}

Conomos, Matthew P. ^{[7
]}

Evans, Daniel S. ^{[13
]}

Frazier-Wood, Alexis C. ^{[14
]}

Gharib, Sina A. ^{[15
]}

Gleason, Kevin J. ^{[1
,16
]}

Gottlieb, Daniel J. ^{[1
,2
,17
]}

Hillman, David R. ^{[18
]}

Johnson, W. Craig ^{[7
]}

Lederer, David J. ^{[19
,20
]}

Lee, Jiwon ^{[1
]}

Loredo, Jose S. ^{[21
]}

Mei, Hao ^{[22
]}

Mukherjee, Sutapa ^{[23
,24
]}

Patel, Sanjay R. ^{[25
]}

Post, Wendy S. ^{[26
]}

Purcell, Shaun M. ^{[1
,2
,3
]}

Ramos, Alberto R. ^{[27
]}

Reid, Kathryn J. ^{[28
]}

Rice, Ken ^{[7
]}

Shah, Neomi A. ^{[29
]}

Sofer, Tamar ^{[1
,2
,7
]}

Taylor, Kent D. ^{[30
,31
]}

Thornton, Timothy A. ^{[7
]}

Wang, Heming ^{[1
,2
,3
]}

Yaffe, Kristine ^{[32
,33
]}

Zee, Phyllis C. ^{[28
]}

Hanis, Craig L. ^{[4
]}

Palmer, Lyle J. ^{[34
]}

Rotter, Jerome, I ^{[30
,31
]}

Stone, Katie L. ^{[13
]}

Tranah, Gregory J. ^{[13
]}

Wilson, James G. ^{[35
]}

Sunyaev, Shamil R. ^{[3
,36
,37
]}

Laurie, Cathy C. ^{[7
]}

Zhu, Xiaofeng ^{[38
]}

Saxena, Richa ^{[1
,2
,3
,39
,40
]}

Lin, Xihong ^{[10
]}

Redline, Susan ^{[1
,2
,41
]}

机构：

[1] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 USA

[2] Harvard Med Sch, Div Sleep Med, Boston, MA 02115 USA

[3] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[4] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA

[5] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Precis Hlth, Houston, TX 77030 USA

[6] Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Ctr Precis Hlth, Houston, TX 77030 USA

[7] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[8] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA

[9] Albert Einstein Coll Med, Div Resp & Sleep Med, Childrens Hosp Montefiore, Bronx, NY 10467 USA

[10] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[11] Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Nashville, TN USA

[12] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Biostat, Chapel Hill, NC 27515 USA

[13] Calif Pacific Med Ctr Res Inst, San Francisco, CA USA

[14] USDA ARS, Childrens Nutr Res Ctr, Baylor Coll Med, Houston, TX USA

[15] Univ Washington, Div Pulm Crit Care & Sleep Med, UW Med Sleep Ctr, Computat Med Core,Ctr Lung Biol, Seattle, WA 98195 USA

[16] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA

[17] VA Boston Healthcare Syst, Boston, MA USA

[18] Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep Med, Perth, WA, Australia

[19] Columbia Univ, Dept Med, New York, NY USA

[20] Columbia Univ, Dept Epidemiol, New York, NY USA

[21] UC San Diego Sch Med, Dept Med, Div Pulm Crit Care & Sleep Med, La Jolla, CA USA

[22] Univ Mississippi, Med Ctr, Dept Data Sci, Jackson, MS 39216 USA

[23] Southern Adelaide Local Hlth Network, Sleep Hlth Serv, Resp & Sleep Serv, Adelaide, SA, Australia

[24] Flinders Univ S Australia, Adelaide Inst Sleep Hlth, Adelaide, SA, Australia

[25] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA

[26] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA

[27] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA

[28] Northwestern Univ, Dept Neurol, Ctr Circadian & Sleep Med, Feinberg Sch Med, Chicago, IL 60611 USA

[29] Icahn Sch Med Mt Sinai, Div Pulm Crit Care & Sleep Med, New York, NY 10029 USA

[30] UCLA Med Ctr, LABioMed Harbor, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA USA

[31] UCLA Med Ctr, LABioMed Harbor, Inst Translat Genom & Populat Sci, Dept Med, Torrance, CA USA

[32] Univ Calif San Francisco, Dept Psychiat Neurol & Epidemiol & Biostat, San Francisco, CA 94143 USA

[33] San Francisco VA Med Ctr, San Francisco, CA USA

[34] Univ Adelaide, Sch Publ Hlth, Adelaide, SA, Australia

[35] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA

[36] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA

[37] Harvard Med Sch, Div Med Sci, Boston, MA 02115 USA

[38] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA

[39] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

[40] Massachusetts Gen Hosp, Dept Anesthesia Pain & Crit Care Med, Boston, MA 02114 USA

[41] Beth Israel Deaconess Med Ctr, Div Pulm Crit Care & Sleep Med, Boston, MA 02215 USA

来源：

PLOS GENETICS | 2019年 / 15卷 / 04期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; NLRP3; INFLAMMASOME; OSTEOPOROTIC FRACTURES; COGNITIVE IMPAIRMENT; INTERMITTENT HYPOXIA; OXYGEN DESATURATION; PULMONARY-FIBROSIS; SEX-DIFFERENCES; APNEA-HYPOPNEA; HEART-FAILURE;

D O I：

10.1371/journal.pgen.1007739

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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 x 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO(2) (rs72805692 p = 4.58 x 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 summary Variation in oxyhemoglobin saturation, the proportion of oxygen-saturated to total hemoglobin in the blood, is associated with numerous disorders and is a predictor of health outcomes including mortality, incident heart failure, and dementia. Despite the fundamental role of oxygen saturation in normal and abnormal physiology, there are few large-scale genetic studies of oxygen saturation performed across populations. Overnight measurements provide more variability than daytime levels due to the stresses associated with normal and disordered breathing, and also provide an important measure of sleep apnea severity, a common disorder in the population that is associated with considerable morbidity. In this study, for the first time, we identified multiple replicated genome-significant associations based on up to 22,736 individuals from 10 cohort studies. Our findings suggest a contribution of inflammatory genes such as the Interleukin 18 receptor subunit genes to the genetic architecture of sleep-disordered breathing. These results extend our understanding of the genetics of oxyhemoglobin saturation and sleep-disordered breathing and may provide further insight into the biology of associated diseases.

引用

页数：31

共 132 条

[1] Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects: The Long Life Family Study (LLFS) [J].

An, Ping ;

Miljkovic, Iva ;

Thyagarajan, Bharat ;

Kraja, Aldi T. ;

Daw, E. Warwick ;

Pankow, James S. ;

Selvin, Elizabeth ;

Kao, W. H. Linda ;

Maruthur, Nisa M. ;

Nalls, Micahel A. ;

Liu, Yongmei ;

Harris, Tamara B. ;

Lee, Joseph H. ;

Borecki, Ingrid B. ;

Christensen, Kaare ;

Eckfeldt, John H. ;

Mayeux, Richard ;

Perls, Thomas T. ;

Newman, Anne B. ;

Province, Michael A. .

METABOLISM-CLINICAL AND EXPERIMENTAL, 2014, 63 (04) :461-468

[2]

[Anonymous], 035170 BIORXIV

[3]

[Anonymous], 2015, Nature, DOI DOI 10.1038/NATURE15393

[4] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[5] Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics [J].

Barbeira, Alvaro N. ;

Dickinson, Scott P. ;

Bonazzola, Rodrigo ;

Zheng, Jiamao ;

Wheeler, Heather E. ;

Torres, Jason M. ;

Torstenson, Eric S. ;

Shah, Kaanan P. ;

Garcia, Tzintzuni ;

Edwards, Todd L. ;

Stahl, Eli A. ;

Huckins, Laura M. ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Im, Hae Kyung .

NATURE COMMUNICATIONS, 2018, 9

[6] Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia [J].

Beall, CM .

INTEGRATIVE AND COMPARATIVE BIOLOGY, 2006, 46 (01) :18-24

[7] RECIPROCAL BINDING OF OXYGEN AND DIPHOSPHOGLYCERATE BY HUMAN HEMOGLOBIN [J].

BENESCH, R ;

BENESCH, RE ;

YU, CI .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1968, 59 (02) :526-&

[8] NLRP3 inflammasome is required in murine asthma in the absence of aluminum adjuvant [J].

Besnard, A. -G. ;

Guillou, N. ;

Tschopp, J. ;

Erard, F. ;

Couillin, I. ;

Iwakura, Y. ;

Quesniaux, V. ;

Ryffel, B. ;

Togbe, D. .

ALLERGY, 2011, 66 (08) :1047-1057

[9] Multi-ethnic study of atherosclerosis: Objectives and design [J].

Bild, DE ;

Bluemke, DA ;

Burke, GL ;

Detrano, R ;

Roux, AVD ;

Folsom, AR ;

Greenland, P ;

Jacobs, DR ;

Kronmal, R ;

Liu, K ;

Nelson, JC ;

O'Leary, D ;

Saad, MF ;

Shea, S ;

Szklo, M ;

Tracy, RP .

AMERICAN JOURNAL OF EPIDEMIOLOGY, 2002, 156 (09) :871-881

[10] Prevalence of sleep-disordered breathing in women - Effects of gender [J].

Bixler, EO ;

Vgontzas, AN ;

Lin, HM ;

Ten Have, T ;

Rein, J ;

Vela-Bueno, A ;

Kales, A .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2001, 163 (03) :608-613

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