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 IS years. 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. (C) 2009 Elsevier B.V. All rights reserved.