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

Author
item CADE, BRIAN - BRIGHAM & WOMEN'S HOSPITAL
item CHEN, HAN - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item STILP, ADRIENNE - UNIVERSITY OF WASHINGTON
item TIN, LOUIE - UNIVERSITY OF WASHINGTON
item ANCOLI-ISRAEL, SONIA - UNIVERSITY OF CALIFORNIA
item ARENS, RAANAN - ALBERT EINSTEIN COLLEGE OF MEDICINE
item BARFIELD, RICHARD - UNIVERSITY OF WASHINGTON
item BELOW, JENNIFER - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item CAI, JIANWEN - UNIVERSITY OF NORTH CAROLINA
item CONOMOS, MATTHEW - UNIVERSITY OF WASHINGTON
item EVANS, DANIEL - CALIFORNIA PACIFIC MEDICAL CENTER
item FRAZIER-WOOD, ALEXIS - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item GHARIB, SINA - UNIVERSITY OF WASHINGTON
item GLEASON, KEVIN - BRIGHAM & WOMEN'S HOSPITAL
item GOTTLIEB, DANIEL - BRIGHAM & WOMEN'S HOSPITAL
item HILLMAN, DAVID - UNIVERSITY OF WESTERN AUSTRALIA
item JOHNSON, W - UNIVERSITY OF WASHINGTON
item LEDERER, DAVID - COLUMBIA UNIVERSITY MEDICAL CENTER
item LEE, JIWON - BRIGHAM & WOMEN'S HOSPITAL
item LOREDO, JOSE - UNIVERSITY OF CALIFORNIA
item MEI, HAO - UNIVERSITY OF MISSISSIPPI MEDICAL CENTER
item MUKHERJEE, SUTAPA - BRIGHAM & WOMEN'S HOSPITAL
item PATEL, SANJAY - UNIVERSITY OF PITTSBURGH MEDICAL CENTER
item POST, WENDY - JOHNS HOPKINS UNIVERSITY
item PURCELL, SHAUN - BRIGHAM & WOMEN'S HOSPITAL
item RAMOS, ALBERTO - UNIVERSITY OF MIAMI
item REID, KATHRYN - NORTHWESTERN UNIVERSITY
item RICE, KEN - UNIVERSITY OF WASHINGTON
item SHAH, NEOMI - THE ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
item SOFER, TAMAR - BRIGHAM & WOMEN'S HOSPITAL
item TAYLOR, KENT - LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE
item THORNTON, TIMOTHY - UNIVERSITY OF WASHINGTON
item WANG, HEMING - BRIGHAM & WOMEN'S HOSPITAL
item YAFFE, KRISTINE - UNIVERSITY OF CALIFORNIA
item ZEE, PHYLLIS - NORTHWESTERN UNIVERSITY
item HANIS, CRAIG - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item PALMER, LYLE - UNIVERSITY OF ADELAIDE
item ROTTER, JEROME - LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE
item STONE, KATIE - UNIVERSITY OF CALIFORNIA
item TRANAH, GREGORY - CALIFORNIA PACIFIC MEDICAL CENTER
item WILSON, JAMES - UNIVERSITY OF MISSISSIPPI MEDICAL CENTER
item SUNYAEV, SHAMIL - BRIGHAM & WOMEN'S HOSPITAL
item LAURIE, CATHY - UNIVERSITY OF WASHINGTON
item ZHU, XIAOFENG - CASE WESTERN RESERVE UNIVERSITY (CWRU)
item SAXENA, RICHA - BRIGHAM & WOMEN'S HOSPITAL
item LIN, XIHONG - HARVARD SCHOOL OF PUBLIC HEALTH
item REDLINE, SUSAN - BRIGHAM & WOMEN'S HOSPITAL

Submitted to: PLoS Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/3/2018
Publication Date: 4/16/2019
Citation: Cade, B.E., Chen, H., Stilp, A.M., Tin, L., 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., Loredo, J.S., Mei, H., Mukherjee, S., Patel, S.R., Post, W.S., Purcell, S.M., Ramos, A.R., Reid, K.J., Rice, K., Shah, N., Sofer, T., Taylor, K.D., Thornton, T.A., Wang, H., Yaffe, K., Zee, P.C., Hanis, C.L., Palmer, L.J., Rotter, J.I., Stone, K.L., Tranah, G.J., Wilson, J.G., Sunyaev, S.R., Laurie, C.C., 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. 15(4):e1007739. https://doi.org/10.1371/journal.pgen.1007739.
DOI: https://doi.org/10.1371/journal.pgen.1007739

Interpretive 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.

Technical 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 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 SpO2 (rs78136548 p=2.70 x 10**-10). SNPs at 10q22 were associated with all three traits including average SpO2 (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.