Hypoxia Inducible Factor1-alpha Genetic Polymorphism of Obstructive Sleep Apnea

Obstructive sleep apnea syndrome (OSAS) is characterized with recurrent collapse of upper airway during sleep and results in chronic intermittent hypoxia, which leads to 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. 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polymorphism could result in increased HIF-1 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, angiotensin converting enzyme and haptoglobin. Only heptoglobin phenotype is proved to be a risk factor for cardiovascular disease in OSA. In most studies, the patient number is less than suggested. In this study, we tested the association between HIF-1gene polymorphism and cardiovascular disease in OSA. By by recruiting 603 patients of OSA (apnea-hypopnea index 15/hr), we examined all regions of the HIF-1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. Therefore, we (1) Identified specific SNPs of HIF-1gene related to cardiovascular disease in OSA patients (CVD-OSA) (2) Assayed the functional activity of high risk SNPs of HIF-1on the transcription of VEGF gene (3) Confirmed 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 finding of our study will be helpful for stratifying the risk of OSA patients to specific outcome, or response to specific therapy.