ASSOCIATION STUDY OF THE 5'-FLANKING REGIONS OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE AND ENDOTHELIAL-1 GENES IN FAMILIAL PRIMARY OPEN-ANGLE GLAUCOMA

1, Endothelium-derived substances are important regulators of the micr ocirculation, Endothelium-derived nitric oxide (Ne), which is catalyse d by nitric oxide synthase (NOS), is a potent modulator of vascular to ne in the human ophthalmic artery, which is normally in a state of con stant vasodilation due to the actions of NO. Endothelin-1 (ET-1) produ ces vasoconstriction of the anterior optic nerve vasculature and may b e associated with glaucomatous optic neuropathy The aetiology of prima ry open-angle glaucoma (POAG) remains largely unknown, Thus, alteratio ns in the regulatory sequences of the genes coding for endothelium-der ived NOS (eNOS) and ET-I map hare important effects in the development of POAG and were looked for in the present study 2, Ln 56 patients wi th familial POAG and in 100 control subjects with no family history of hypertension or POAG, we examined the 5' flanking sequences of the eN OS and FT-I genes, which contain many positive and negative regulatory regions affecting gene transcription, using polymerase chain reaction -based single strand conformation polymorphism analysis, to search for alterations, No variant in the promoter region of the ET-1 gene was o bserved in familial POAG or controls, Using three primer sets spanning 706 b.p. of the eNOS gene, we observed alterations in II of 56 (20%) familial POAG members and in seven of 100 (7%) controls, Sequence anal ysis demonstrated a C/T substitution at the 5' sequence position nucle otide (nt) -690 from the transcription start site, which lies between the cAMP regulatory element (nt -726 to -732) and an activator protein -1 binding domain (nt -655 to -661), 3, in summary, genotypic and alle lic frequency analysis found no association between alterations in the promoter region of the ET-1 gene and familial POAG. A variant in the promoter region of the eNOS gene was seen in a significant percentage of familial POAG patients, Future expression studies will determine wh ether this polymorphism results in altered eNOS gene expression.