Hypoxia Inducible factor1-Alpha Genetic Polymorphism of Obstructive Sleep Apnea

Specific Aim

1. To identify specific SNPs of HIF-1 gene related to cardiovascular disease in OSA patients (CVD-OSA)
2. To assay the functional activity of high risk SNPs of HIF-1 on the transcription of VEGF gene
3. To confirm that the serum level of VEGF in CVD-OSA patients with high risk SNPs of HIF-1 are higher than CVD-OSA patients without

Study Overview

• Status: Unknown
• Conditions: Sleep Apnea, Obstructive

Detailed Description

Obstructive sleep apnea syndrome(OSAS) is characterized with recurrent collapse of upper airway during sleep and results in hypoxia and sleep fragmentation. The repeated episodes of hypoxia and sympathetic hyperactivity result in cardiovascular complications, including atherosclerosis, hypertension, coronary artery disease and heart failure. Our data showed among 309 consecutively-admitted OSA patients, 54% patients had cardiovascular diseases.

The hypoxia in OSA is characterized as chronic and intermittent, which leads to sophisticated adaptive mechanisms, like activations of transcriptional factors and critical signaling pathways. HIF-1 is a central component of transcriptional factors involved in hypoxia-induced transcription of specific genes. There are two subunits of HIF-1 transcription factor, which interact with the consensus hypoxia response element in the target genes. The HIF-1 alpha activity is regulated by proline hydroxylation modification and ubiquitination, which is oxygen-tension dependent. HIF-1 alpha target genes encode proteins that increase oxygen delivery, such as vascular endothelial growth factor(VEGF). Our oligo-microarray study showed both HIF and VEGF expression in OSA patients was 1.3 times of control group, which decreased to 46% and 57% respectively after one-month CPAP treatment.

HIF-1 alpha polymorphism could result in increased HIF-1 alpha activity and microvessel density. In clinical observation, HIF-1 polymorphism has been reported to be associated with high altitude adaptation, formation of coronary collaterals in CAD and phenotype of cancer. These findings were possibly explained with effect of HIF on modulation of VEGF.

Several genetic polymorphisms were reported to be associated with OSA, which included TNF alpha, angiotensin converting enzyme and haptoglobin. Only hepatoglobin phenotype is proved to be a risk factor for cardiovascular disease in OSA. In most studies, the patient number is less than suggested.

Therefore, in this study, we hypothesized that HIF-1 gene polymorphism was associated with cardiovascular disease in OSA. And by using large-scale of study population(1000 OSA patients), we examined all regions of the HIF-1 alpha to detect single-nucleotide polymorphisms(SNPs), evaluated the pattern of linkage disequilibrium to compose haplotypes in the gene, and performed association studies in OSA patients with and without cardiovascular disease to achieve the following 3 objectives:(1)To identify specific SNPs of HIF-1 alpha gene related to cardiovascular disease in OSA patients (CVD-OSA).(2)To assay the functional activity of high risk SNPs of HIF-1 alpha on the transcription of VEGF gene.(3)To confirm that the serum level of VEGF in CVD-OSA patients with high risk SNPs of HIF-1 are higher than CVD-OSA patients without. The findings are expected to stratify the risk of OSA patients to specific outcome, or response to specific therapy.

• Study Type: Observational
• Enrollment (Anticipated): 1000

Contacts and Locations

• Study Contact: Name: Peilin Lee, M.D.; Phone Number: +886-2-23562905; Email: peilin1986@yahoo.com.tw

Study Locations

• Taiwan
  • Taipei, Taiwan
    • Recruiting
    • National Taiwan Univeristy Hospital
    • Contact: Peilin Lee, M.D.; Phone Number: +886-2-23562905; Email: peilin1986@yahoo.com.tw
    • Sub-Investigator: Peilin Lee, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

patients referred sleep center to rule out obstructive sleep apnea

Description

Inclusion Criteria:

• Severe obstructive sleep apnea (AHI>=30/hr) age, sex, BMI match control subject

Exclusion Criteria:

• Patients were excluded when: (1) refused to participate in this study, (2) had severe obstructive pulmonary disease or active neurological events, (3) enrolled in other studies at the same time

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Principal Investigator: Hey-Dong Wu, M.D., National Taiwan University Hospital

Publications and helpful links

General Publications

• Pandit JJ. Structure-function relationships: a breath of fresh air--or just more hot air--in sleep apnoea research? Respiration. 2008;76(1):16-8. doi: 10.1159/000127578. Epub 2008 May 8. No abstract available.

Study record dates

Study Major Dates

• Study Start: March 1, 2006

Study Registration Dates

• First Submitted: July 8, 2007
• First Submitted That Met QC Criteria: July 8, 2007
• First Posted (Estimate): July 10, 2007

Study Record Updates

• Last Update Posted (Estimate): January 14, 2009
• Last Update Submitted That Met QC Criteria: January 12, 2009
• Last Verified: January 1, 2009

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Sleep Apnea, Obstructive
• Other Study ID Numbers: 9561701013