Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study

Abstract

The endothelins are among the most potent vasoconstrictors known. Pharmacological inhibition of endothelin receptors lowers blood pressure (BP). It is unknown whether naturally occurring genetic variation in the endothelin receptors influences BP. We have evaluated the type A endothelin receptor (EDNRA) as a candidate gene for hypertension in a large family study. A total of 1425 members of 248 families selected via a proband with hypertension were studied. Ambulatory BP monitoring was conducted using the A&D TM2421 device. Four haplotype-tagging single nucleotide polymorphisms (SNPs) spanning the EDNRA gene were typed. There was evidence of association between genotype at the rs5335 (C þ 70G) SNP and night systolic blood pressure ( þ 1.24% (s.e. 0.64) per G allele; P ¼ 0.05); night diastolic blood pressure ( þ 1.64% (s.e. 0.71) per G allele; P ¼ 0.021) and night mean BP ( þ 1.51% (s.e. 0.64) per G allele; P ¼ 0.017). Borderline significant trends in the same direction were seen for daytime BPs. Proportions of hypertensives in each of the three genotype groups were C/C 34.7%, C/G 37.9%, G/G 42.4% yielding an odds ratio for hypertension per G allele of 1.19 (95% confidence interval 1.00-1.41; P ¼ 0.05). In conclusion, the rs5335 (C þ 70G) polymorphism of the EDNRA gene has small effects on the risk of hypertension. Natural variation in other genes in the endothelin-signalling pathway should be explored to identify additional influences on BP regulation.

Endothelin Type A Receptor Genotype is a Determinant of Quantitative Traits of Metabolic Syndrome in Asian Hypertensive Families: A SAPPHIRe Study

“…Our findings supported and extended the prior observations in Caucasians (23, 24, 29) that there is no significant association of this solely gene polymorphism with BP. On the contrary, some other polymorphisms of ETS have been shown to be associated with BP either directly or in interaction with other genes/factors, for example C1363T in exon 8 of the ET A receptor on pulse pressure of normotension (24), G198T in exon 5 of the ET-1 gene together with BMI on BP (26), and A985G in 3′-untranslated region of the ET-2 gene on the severity of hypertension (41).…”

“…To date, genetic variations and association studies of this putative hypertension gene (23–25, 29, 39) have been performed mostly in subjects of European ancestry but not in Asian origins excepta few literature regarding Japanese (26, 40). Therefore, we conducted this study to investigate whether the T323C polymorphism of the gene encoded for ET A receptor might be involved in the predisposition in IR-associated hypertension in a large Asian cohort ascertained via essential hypertension.…”

“…Though examining sole single nucleotide polymorphism might have limitations of interpretation, study on combination of four common haplotype blocks merely revealed mild effect on the risk of hypertension (29). It should be noted that this variant located within codon 323 in the sixth exon of ET A receptor gene is a silent polymorphism (CAT → CAC, His → His).…”

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

“…Because of the role of endothelin as a potent vasoconstrictor, the endothelin receptor, type A is a target for pharmacologic treatments to reduce blood pressure. 26 In addition, variation in the gene was associated with blood pressure 27 , atherosclerosis 28 and cardiovascular disease endpoints 29 in candidate gene studies.…”

Candidate Genes in Hypertension

“…The substitution of a thymine for a cytosine located in the untranslated part of exon 8 of the ET-RA gene was associated with pulse pressure and hypertension . In addition, an association was reported between genotype at the rs5335 (C+70G) SNP and night systolic BP and diastolic BP (Rahman et al, 2008). In this study the rs5335 (C+70G) polymorphism of the ET-RA receptor gene has small effects on the risk of hypertension.…”