Quantitative association between a newly identified molecular variant in the endothelin-2 gene and human essential hypertension

Background Essential hypertension is a multifactorial disease in which the genetic contribution is probably the result of a number of genes acting in combination. Recent work has incriminated endothelin-2 (ET2) as a candidate gene for human essential hypertension. This study sought to (i) determine the existence of any molecular Variants in the ET2 gene; (ii) undertake an allelic-association study of any such variants found in a large group of we ll characterized hypertensive and control populations; and (iii) assess any quantitative relationship between the molecular variant and pretreatment b lood presure. Methods The ET2 gene was subjected to single strand conformation polymorphi sm (SSCP) analysis in order to identify novel molecular variants. Well-char acterized subjects recruited from our local population were used in our ass ociation study. Two hundred and forty-four hypertensive patients with pre-t reatment blood pressure (range 139/94-237/133 mmHg) were well matched with 228 controls from our local population of 30 000 healthy subjects (range 96 /62-160/85 mmHg). All subjects were Caucasian. Results Polymerase chain reaction-SSCP identified a single A985G base chang e in 3'-UTR of the ET2 gene which was confirmed by direct sequencing. A res triction site for the enzyme BsmA1 was either created (+) or removed (-) wi th this polymorphism. Analysis of variance showed that the ET2 genotype was an independent predictor of pre-treatment diastolic blood pressure (DBP) i n the hypertensive (P< 0.001) but not normotensive group with higher pressu res tracking with the (-) allele. Other covariates such as age, sex, alcoho l, cigarette smoking, body mass index and cholesterol showed no significant relationship with this genotype. The genotype frequencies for the hyperten sive and control population were (-/-: -/+: +/+)178:58:8 and 168:55: 5, res pectively (not significant). Subjects from the top and tail quartiles of me asurement of blood pressure in both groups were selected for genotype and a llele frequency comparison. Both genotype and allele differences were highl y significant between the two extreme groups for DBP (genotype P< 0.001, al leles P< 0.01) distribution. A search for potential functional variants in linkage disequilibrium with A985G found one further variant in the 5'-UTR, C44T, Conditional haplotype probabilities in 214 chromosomes show that this polymorphism is not in linkage disequilibrium with the 3'-UTR. No other va riants were found on a molecular screen of the transcribed portion of the E T2 gene. Conclusion This newly identified polymorphism of the ET2 gene tracked signi ficantly in hypertensives when blood pressure was assessed as a quantitativ e trait. The difference in genotype and allele frequencies between the extr emes of blood pressure suggest that the ET2 locus influences the severity r ather than the initial development of hypertension. J Hypertens 1999, 17:12 81-1287 (C) Lippincott Williams & Wilkins.