title: Analysis of Hypoxic and Hypercapnic Ventilatory Response in Healthy Volunteers.
abstract: BACKGROUND
  A previous study has suggested that the Human Leukocyte Antigen (HLA) allele DQB1*06:02 affects hypoxic ventilatory response (HVR) but not hypercapnic ventilatory response (HCVR) in an Asian population. The current study evaluated the relationship in Caucasians and Asians. In addition we assessed whether gender or polymorphisms in genes participating in the control of breathing affect HVR and HCVR.
  
  
  METHODS
  A re-breathing system was used to measure HVR and HCVR in 551 young adults (56.8% Caucasians, 30% Asians). HLA-DQB1*06:02 and tagged polymorphisms and coding variants in genes participating in breathing (PHOX2B, GPR4 and TASK2/KCNK5) were analyzed. The associations between HVR/HCVR and HLA-DQB1*06:02, genetic polymorphisms, and gender were evaluated using ANOVA or frequentist association testing with SNPTEST.
  
  
  RESULTS
  HVR and gender are strongly correlated. HCVR and gender are not. Mean HVR in women was 0.276±0.168 (liter/minute/%SpO2) compared to 0.429±0.266 (liter/minute/%SpO2) in men, p<0.001 (55.4% higher HVR in men). Women had lower baseline minute ventilation (8.08±2.36 l/m vs. 10.00±3.43l/m, p<0.001), higher SpO2 (98.0±1.3% vs. 96.6±1.7%, p<0.001), and lower EtCO2 (4.65±0.68% vs. 4.82±1.02%, p = 0.025). One hundred and two (18.5%) of the participants had HLA-DQB1*06:02. No association was seen between HLA-DQB1*06:02 and HVR or HCVR. Genetic analysis revealed point wise, uncorrected significant associations between two TASK2/KCNK5 variants (rs2815118 and rs150380866) and HCVR.
  
  
  CONCLUSIONS
  This is the largest study to date reporting the relationship between gender and HVR/ HCVR and the first study assessing the association between genetic polymorphisms in humans and HVR/HCVR. The data suggest that gender has a large effect on hypoxic breathing response.
authors.affiliation: Pediatric Pulmonology Unit, Shaare Zedek Medical Center, Hebrew University, School of Medicine, Jerusalem, Israel.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Goldberg
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA, United States of America.
authors.forename: Hanna Maria
authors.initials: HM
authors.lastname: Ollila
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA, United States of America.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA, United States of America.
authors.forename: Husham
authors.initials: H
authors.lastname: Sharifi
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA, United States of America.
authors.forename: Tom
authors.initials: T
authors.lastname: Rico
authors.affiliation: East London NHS Foundation Trust, Newham Centre for Mental Health, London, United Kingdom.
authors.forename: Olivier
authors.initials: O
authors.lastname: Andlauer
authors.affiliation: Neuropediatric unit, Shaare Zedek Medical Center, Hebrew University, School of Medicine, Jerusalem, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Aran
authors.affiliation: Department of Family Medicine, Hebrew University and Clalit Health Services, Jerusalem, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Bloomrosen
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA, United States of America.
authors.forename: Juliette
authors.initials: J
authors.lastname: Faraco
authors.affiliation: Department of Pulmonary Medicine, Peking University People's Hospital, Beijing, China.
authors.forename: Han
authors.initials: H
authors.lastname: Fang
authors.affiliation: Stanford University Center for Sleep Sciences, Palo Alto, CA, United States of America.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D044466:Asian People; D005260:Female; D005838:Genotype; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D064368:Healthy Volunteers; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D006935:Hypercapnia / Q000208:ethnology / Q000235:genetics*; D000860:Hypoxia / Q000208:ethnology / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012119:Respiration; D012737:Sex Factors; D014157:Transcription Factors / Q000235:genetics; D012122:Ventilators, Mechanical; D044465:White People; D055815:Young Adult
chemical_list: C091670:GPR4 protein, human; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D018398:Homeodomain Proteins; C410295:KCNK5 protein, human; C109220:NBPhox protein; D024683:Potassium Channels, Tandem Pore Domain; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors