Association of Genetic Loci with Sleep Apnea in European Americans and African-Americans: The Candidate Gene Association Resource (CARe)

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Abstract

Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study.

Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×10 ⁻⁶. Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts.

Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis.

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Most cited references 34

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Prospective study of the association between sleep-disordered breathing and hypertension.

Paul E. Peppard, Terry Young, Mari Palta … (2000)

Sleep-disordered breathing is prevalent in the general population and has been linked to chronically elevated blood pressure in cross-sectional epidemiologic studies. We performed a prospective, population-based study of the association between objectively measured sleep-disordered breathing and hypertension (defined as a laboratory-measured blood pressure of at least 140/90 mm Hg or the use of antihypertensive medications). We analyzed data on sleep-disordered breathing, blood pressure, habitus, and health history at base line and after four years of follow-up in 709 participants of the Wisconsin Sleep Cohort Study (and after eight years of follow-up in the case of 184 of these participants). Participants were assessed overnight by 18-channel polysomnography for sleep-disordered breathing, as defined by the apnea-hypopnea index (the number of episodes of apnea and hypopnea per hour of sleep). The odds ratios for the presence of hypertension at the four-year follow-up study according to the apnea-hypopnea index at base line were estimated after adjustment for base-line hypertension status, body-mass index, neck and waist circumference, age, sex, and weekly use of alcohol and cigarettes. Relative to the reference category of an apnea-hypopnea index of 0 events per hour at base line, the odds ratios for the presence of hypertension at follow-up were 1.42 (95 percent confidence interval, 1.13 to 1.78) with an apnea-hypopnea index of 0.1 to 4.9 events per hour at base line as compared with none, 2.03 (95 percent confidence interval, 1.29 to 3.17) with an apnea-hypopnea index of 5.0 to 14.9 events per hour, and 2.89 (95 percent confidence interval, 1.46 to 5.64) with an apnea-hypopnea index of 15.0 or more events per hour. We found a dose-response association between sleep-disordered breathing at base line and the presence of hypertension four years later that was independent of known confounding factors. The findings suggest that sleep-disordered breathing is likely to be a risk factor for hypertension and consequent cardiovascular morbidity in the general population.

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Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study.

José M. Marin, Santiago Carrizo, Eugenio Vicente … (2005)

The effect of obstructive sleep apnoea-hypopnoea as a cardiovascular risk factor and the potential protective effect of its treatment with continuous positive airway pressure (CPAP) is unclear. We did an observational study to compare incidence of fatal and non-fatal cardiovascular events in simple snorers, patients with untreated obstructive sleep apnoea-hypopnoea, patients treated with CPAP, and healthy men recruited from the general population. We recruited men with obstructive sleep apnoea-hypopnoea or simple snorers from a sleep clinic, and a population-based sample of healthy men, matched for age and body-mass index with the patients with untreated severe obstructive sleep apnoea-hypopnoea. The presence and severity of the disorder was determined with full polysomnography, and the apnoea-hypopnoea index (AHI) was calculated as the average number of apnoeas and hypopnoeas per hour of sleep. Participants were followed-up at least once per year for a mean of 10.1 years (SD 1.6) and CPAP compliance was checked with the built-in meter. Endpoints were fatal cardiovascular events (death from myocardial infarction or stroke) and non-fatal cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, coronary artery bypass surgery, and percutaneous transluminal coronary angiography). 264 healthy men, 377 simple snorers, 403 with untreated mild-moderate obstructive sleep apnoea-hypopnoea, 235 with untreated severe disease, and 372 with the disease and treated with CPAP were included in the analysis. Patients with untreated severe disease had a higher incidence of fatal cardiovascular events (1.06 per 100 person-years) and non-fatal cardiovascular events (2.13 per 100 person-years) than did untreated patients with mild-moderate disease (0.55, p=0.02 and 0.89, p<0.0001), simple snorers (0.34, p=0.0006 and 0.58, p<0.0001), patients treated with CPAP (0.35, p=0.0008 and 0.64, p<0.0001), and healthy participants (0.3, p=0.0012 and 0.45, p<0.0001). Multivariate analysis, adjusted for potential confounders, showed that untreated severe obstructive sleep apnoea-hypopnoea significantly increased the risk of fatal (odds ratio 2.87, 95%CI 1.17-7.51) and non-fatal (3.17, 1.12-7.51) cardiovascular events compared with healthy participants. In men, severe obstructive sleep apnoea-hypopnoea significantly increases the risk of fatal and non-fatal cardiovascular events. CPAP treatment reduces this risk.

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Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force.

W. T. McNicholas, K. P. Strohl, D White … (1999)

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Author and article information

Contributors

Francisco José Esteban: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 14 November 2012

Volume: 7

Issue: 11

Electronic Location Identifier: e48836

Affiliations

[1 ]Division of Sleep Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America

[2 ]Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America

[3 ]Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America

[4 ]Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

[5 ]Jackson Heart Study, Jackson, Mississippi, United States of America

[6 ]Department of Epidemiology and Biostatistics, Jackson State University, Jackson, Mississippi, United States of America

[7 ]Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America

[8 ]University of Washington Medicine Sleep Center and Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, United States of America

[9 ]Veterans Affairs Boston Healthcare System, Boston, Massachusetts, United States of America

[10 ]Framingham Heart Study, Framingham, Massachusetts, United States of America

[11 ]Department of Medicine, Boston University, Boston, Massachusetts, United States of America

[12 ]West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Perth, Australia

[13 ]Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America

[14 ]Department of Health Studies, University of Chicago, Chicago, Illinois, United States of America

[15 ]Department of Family Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America

[16 ]Department of Medicine, University of Toronto, Toronto, Ontario, Canada

[17 ]Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada

[18 ]Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America

[19 ]Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America

University of Jaén, Spain

Author notes

* E-mail: spatel@ 123456partners.org

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: SRP SGB TF SAG DJG EKL DSL LL SM LP PZ XZ SR. Performed the experiments: SRP DJG DH LL SM SR. Analyzed the data: SRP RG GD MK JW BC XZ. Wrote the paper: SRP SR.

Article

Publisher ID: PONE-D-12-11514

DOI: 10.1371/journal.pone.0048836

PMC ID: 3498243

PubMed ID: 23155414

SO-VID: 2f7f26e8-8622-4664-81c9-d5867e9a50d1

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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

History

Date received : 20 April 2012

Date accepted : 1 October 2012

Page count

Pages: 10

Funding

The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by UL1RR025005. The Case Transdisciplinary Research in Energetics and Cancer Colon Polyps Study is funded by National Cancer Institute grant CA116867. The Case Sleep Apnea study was funded by NHLBI grant HL081385. The Cleveland Family Study was funded by NHLBI grant HL46380. The Cardiovascular Health Study was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and NHLBI grant HL080295, with additional contribution from National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute of Aging. The Sleep Heart Health Study was funded by NHLBI grant HL94092. The Western Australia Sleep Health Study was supported by the Sir Charles Gairdner and Hollywood Private Hospital Research Foundations, the State Health Research Advisory Council of Western Australia, the Western Australian Sleep Disorders Research Institute and the Centre for Genetic Epidemiology and Biostatistics at the University of Western Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Association of Genetic Loci with Sleep Apnea in European Americans and African-Americans: The Candidate Gene Association Resource (CARe)

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Most cited references 34

Prospective study of the association between sleep-disordered breathing and hypertension.

Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study.

Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force.

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