Genetic polymorphisms in endothelin-receptor-subtype-a-gene as susceptibility factor for obstructive sleep apnea syndrome

Introduction: Traits of obstructive sleep apnea syndrome (OSAS) such as impaired ventilatory control, craniofacial abnormalities, and concomitant cardiovascular diseases are associated with modified endothelin-1 gene (EDN-1) or endothelin-receptor-subtype-a (EDNRA) gene. The endothelin system regulates the cardiovascular homeostasis. EDN-1 interacts mainly with EDNRA for signal transduction. In our study we investigate associations of EDNRA-polymorphisms (four frequent polymorphisms with an allele frequency >5%) and OSAS severity.

Methods: Three hundred ninety-three patients older than 18years, of Caucasian origin and with OSAS (AHI>5/h and daytime sleepiness) were investigated by cardiorespiratory polysomnography. In addition 58 control subjects with healthy sleep were recruited from nearly 300 volunteers. We analysed the EDNRA-polymorphisms E335E, H323H, G-231A and G+70C by polymerase-chain-reaction, restriction-fragment-length-polymorphism and real-time-PCR.

Results: Carrier of the mutant G-231A allele had a significantly lower AHI (p=0.03, OR 0.53, 95% CI 0.3-0.94) when comparing patients and controls. When comparing OSAS severity groups without controls we could not detect significant correlations for the four investigated EDNRA-polymorphisms. Our data confirm that BMI (p<0.001) and male gender (p=0.02) are significantly associated with AHI. The allele frequencies were similar.

Discussion: The genetic investigation of OSA remains important. Our control group was relatively small and we investigated 4 reasonable candidates out of more than 100 EDNRA-polymorphisms. The detected protective effect of the mutant G-231A allele needs further confirmation. Gene based research in OSAS should use genome wide scan and should still consider the endothelin system.