title: Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level.
abstract: Genetic determinants of sleep-disordered breathing (SDB), a common set of disorders that contribute to significant cardiovascular and neuropsychiatric morbidity, are not clear. Overnight nocturnal oxygen saturation (SaO2) is a clinically relevant and easily measured indicator of SDB severity but its genetic contribution has never been studied. Our recent study suggests nocturnal SaO2 is heritable. We performed linkage analysis, association analysis and haplotype analysis of average nocturnal oxyhaemoglobin saturation in participants in the Cleveland Family Study (CFS), followed by gene-based association and additional tests in four independent samples. Linkage analysis identified a peak (LOD = 4.29) on chromosome 8p23. Follow-up association analysis identified two haplotypes in angiopoietin-2 (ANGPT2) that significantly contributed to the variation of SaO2 (P = 8 × 10-5) and accounted for a portion of the linkage evidence. Gene-based association analysis replicated the association of ANGPT2 and nocturnal SaO2. A rare missense SNP rs200291021 in ANGPT2 was associated with serum angiopoietin-2 level (P = 1.29 × 10-4), which was associated with SaO2 (P = 0.002). Our study provides the first evidence for the association of ANGPT2, a gene previously implicated in acute lung injury syndromes, with nocturnal SaO2, suggesting that this gene has a broad range of effects on gas exchange, including influencing oxygenation during sleep.
authors: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors: Heming
authors: H
authors: Wang
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.|Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
authors: Brian E
authors: BE
authors: Cade
authors: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors: Han
authors: H
authors: Chen
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.|Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
authors: Kevin J
authors: KJ
authors: Gleason
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.|Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.|Center for Human Genetic Research and Department of Anesthesia, Pain, and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors: Richa
authors: R
authors: Saxena
authors: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors: Tao
authors: T
authors: Feng
authors: Department of Medicine, Division of Allergy, Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Emma K
authors: EK
authors: Larkin
authors: Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA.|Framingham Heart Study, Framingham, MA.
authors: Ramachandran S
authors: RS
authors: Vasan
authors: Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors: Honghuang
authors: H
authors: Lin
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.|Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.|Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors: Sanjay R
authors: SR
authors: Patel
authors: Department of Pathology & Laboratory Medicine, University of Vermont, Burlington, VT, USA.
authors: Russell P
authors: RP
authors: Tracy
authors: Epidemiology and Prevention Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors: Yongmei
authors: Y
authors: Liu
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.|Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.|Sleep Disorders Center, VA Boston Healthcare System, Boston, MA, USA.
authors: Daniel J
authors: DJ
authors: Gottlieb
authors: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: Jennifer E
authors: JE
authors: Below
authors: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: Craig L
authors: CL
authors: Hanis
authors: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: Lauren E
authors: LE
authors: Petty
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.|Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Shamil R
authors: SR
authors: Sunyaev
authors: Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
authors: Alexis C
authors: AC
authors: Frazier-Wood
authors: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors: Jerome I
authors: JI
authors: Rotter
authors: Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
authors: Wendy
authors: W
authors: Post
authors: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors: Xihong
authors: X
authors: Lin
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.|Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.|Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors: Susan
authors: S
authors: Redline
authors: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors: Xiaofeng
authors: X
authors: Zhu
mesh_terms: D000328:Adult; D042702:Angiopoietin-2 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000235:genetics*; D010108:Oxyhemoglobins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012119:Respiration / Q000235:genetics; D012890:Sleep / Q000235:genetics; D012891:Sleep Apnea Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D010108:Oxyhemoglobins; D010100:Oxygen