04619nas a2201021 4500008004100000022001400041245012900055210006900184260001200253300001300265490000700278520172700285653001502012653001002027653000902037653002202046653003802068653002602106653003402132653001102166653002902177653002202206653003402228653001502262653001102277653001202288653004202300653000902342653001602351653002602367653005002393653001102443653001902454653003602473653002802509653002602537653001002563653002602573653001602599100001902615700001402634700002302648700001502671700002502686700001802711700002202729700002302751700001702774700002402791700002102815700002802836700002002864700002202884700002402906700002202930700001902952700002202971700001502993700002003008700001303028700002203041700002103063700001903084700002203103700002203125700002103147700001403168700001903182700001703201700002003218700002503238700001703263700002003280700002003300700002003320700002003340700002203360700002003382700002303402700002103425700002303446700002103469700001803490700001803508700001603526700001903542856003603561 2019 eng d a1553-740400aAssociations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.0 aAssociations of variants In the hexokinase 1 and interleukin 18 c2019 04 ae10077390 v153 a
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.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aCell Adhesion Molecules, Neuronal10aComputational Biology10aExtracellular Matrix Proteins10aFemale10aGene Regulatory Networks10aGenetic Variation10aGenome-Wide Association Study10aHexokinase10aHumans10aHypoxia10aInterleukin-18 Receptor alpha Subunit10aMale10aMiddle Aged10aNerve Tissue Proteins10aNLR Family, Pyrin Domain-Containing 3 Protein10aOxygen10aOxyhemoglobins10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aSerine Endopeptidases10aSleep10aSleep Apnea Syndromes10aYoung Adult1 aCade, Brian, E1 aChen, Han1 aStilp, Adrienne, M1 aLouie, Tin1 aAncoli-Israel, Sonia1 aArens, Raanan1 aBarfield, Richard1 aBelow, Jennifer, E1 aCai, Jianwen1 aConomos, Matthew, P1 aEvans, Daniel, S1 aFrazier-Wood, Alexis, C1 aGharib, Sina, A1 aGleason, Kevin, J1 aGottlieb, Daniel, J1 aHillman, David, R1 aJohnson, Craig1 aLederer, David, J1 aLee, Jiwon1 aLoredo, Jose, S1 aMei, Hao1 aMukherjee, Sutapa1 aPatel, Sanjay, R1 aPost, Wendy, S1 aPurcell, Shaun, M1 aRamos, Alberto, R1 aReid, Kathryn, J1 aRice, Ken1 aShah, Neomi, A1 aSofer, Tamar1 aTaylor, Kent, D1 aThornton, Timothy, A1 aWang, Heming1 aYaffe, Kristine1 aZee, Phyllis, C1 aHanis, Craig, L1 aPalmer, Lyle, J1 aRotter, Jerome, I1 aStone, Katie, L1 aTranah, Gregory, J1 aWilson, James, G1 aSunyaev, Shamil, R1 aLaurie, Cathy, C1 aZhu, Xiaofeng1 aSaxena, Richa1 aLin, Xihong1 aRedline, Susan uhttps://chs-nhlbi.org/node/8044