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Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep
- Cade, Brian E;
- Chen, Han;
- Stilp, Adrienne M;
- Louie, Tin;
- Ancoli-Israel, Sonia;
- Arens, Raanan;
- Barfield, Richard;
- Below, Jennifer E;
- Cai, Jianwen;
- Conomos, Matthew P;
- Evans, Daniel S;
- Frazier-Wood, Alexis C;
- Gharib, Sina A;
- Gleason, Kevin J;
- Gottlieb, Daniel J;
- Hillman, David R;
- Johnson, W Craig;
- Lederer, David J;
- Lee, Jiwon;
- Loredo, Jose S;
- Mei, Hao;
- Mukherjee, Sutapa;
- Patel, Sanjay R;
- Post, Wendy S;
- Purcell, Shaun M;
- Ramos, Alberto R;
- Reid, Kathryn J;
- Rice, Ken;
- Shah, Neomi A;
- Sofer, Tamar;
- Taylor, Kent D;
- Thornton, Timothy A;
- Wang, Heming;
- Yaffe, Kristine;
- Zee, Phyllis C;
- Hanis, Craig L;
- Palmer, Lyle J;
- Rotter, Jerome I;
- Stone, Katie L;
- Tranah, Gregory J;
- Wilson, James G;
- Sunyaev, Shamil R;
- Laurie, Cathy C;
- Zhu, Xiaofeng;
- Saxena, Richa;
- Lin, Xihong;
- Redline, Susan
- Editor(s): Montgomery, Courtney G
- et al.
Published Web Location
https://doi.org/10.1371/journal.pgen.1007739Abstract
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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