Screening of the endothelin1 gene (EDN1) in a cohort of patients with essential left ventricular hypertrophy.

Abstract

SummaryOur objective was to analyse the role of endothelin1 gene (EDN1) variation in essential left ventricular hypertrophy (LVH). We searched for EDN1 variants in 145 Spanish patients with an essential form of LVH (not secondary to hypertension, aortic stenosis, or any other disease that could explain the hypertrophy). The five EDN1 coding exons and 1.5 kilobases of the promoter region were analysed through single strand conformation analysis and direct sequencing. We found four nucleotide changes: -1224 C/A (promoter), -131 ins/del A (exon 1, 5 -non-translated sequence), A/G in codon 106 (exon 3, silent), and G/T in codon 198 (exon 5, lys198asn). To determine the association between these polymorphisms and cardiac hypertrophy, we compared the genotype frequencies from these 145 patients with 250 healthy controls. We found a higher frequency of patients homozygous for 198 lys (198 KK) (65% vs. 52%; p = 0.01; OR = 1.76) and for -1224 AA (73% vs. 66%; p = 0.19). Homozygotes for -1224 A + 198 K (AA+KK) were significantly more frequent in patients (62% vs. 45%; p = 0.0007; OR = 2.10; 95% CI = 1.35-3.25). The expression of the -1224 C/A and exon 5 K198N variants was analysed with cells in culture. These in vitro studies showed that these variations did not differ in their expression levels. In conclusion, our work has shown that EDN1 variation, and in particular homozygosity for the -1224A/198K haplotype, is associated with the risk of developing cardiac hypertrophy. However, these EDN1 variants do not affect in vitro gene expression.

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

“…In DS-5, Adm mRNA increased in ST88-14 but was downregulated by siNRas, and these alterations in gene expression could serve as the mechanistic basis for an NF1-related cardiovascular disease study. We observed Edn1 mRNA to be highly expressed in ST88-14 (DS-6), and EDN1 has been reported to play an important role in heart development (56) and has been associated with cardiac hypertrophy in patient cohort studies (57). These findings shed light on neurofibromin-NRAS-ADM and neurofibromin-MEK1/2-EDN1 axes identified in MPNST cells in this study, and could expand our understanding of molecular mechanisms for cardiovascular diseases in NF1 patients.…”

Lack of Association between Endothelin-1 Gene Variants and Myocardial Infarction

“…The 974 A allele created a binding site for C/EBPb, a nuclear factor member of the C/EBP family involved in IL-6 expression. Despite this evidence of differential binding to this transcription factor, we had previously reported a lack of effect of the 974 C/A SNP on in vitro gene expression 22) . In agreement with this negative functional effect, we did not find differences in allele/genotype frequencies between MI patients and controls for EDN1 promoter polymorphisms.…”

“…Thirty patients and 30 controls were subjected to direct sequencing in an ABI310 automated system, using BigDye chemistry (Applied Biosystems, Foster City, CA, USA). An additional set of 100 patients and 100 controls was analysed through SSCA, as previously reported 22) . The variation in an additional group of 100 patients and 100 controls was determined through DHPLC using a Varian Helix System and with a linear binary gradient created with buffers Varian Helix A (triethylammonium amine − TEAA) and B (TEAA 25% acetonitrile) (www.varianinc.org).…”

“…The promoter 974 C/A and exon 1 120 ins/ del A polymorphisms were genotyped by PCR-RFLP or SSCA as previously reported 22) . The 1617 T/C polymorphism in the 3´ UTR was genotyped by PCR-RFLP: the DNA was amplified with primers E5F3/ E5R3 ( Table 2) and digested with the restriction enzyme SspI (restriction site, AAT/ATT), followed by electrophoresis on 2% agarose gels.…”

Endothelin-1 Gene Polymorphisms rs5370, rs1476046, and rs3087459 are not Associated with Diabetic Nephropathy in Caucasians with Type 2 Diabetes Mellitus

“…EDN1 has been identifi ed as a strong candidate gene for cardiovascular and renal disease. Various single nucleotide polymorphisms (SNPs) in the EDN1 gene were linked to arterial hypertension 22,23 , heart failure 24 , coronary artery disease 25,26 , left ventricular hypertrophy 27 , modifi cation of vascular reactivity 28 , endothelial dysfunction 29 , progression of atherosclerosis 30 , as well as with accelerated decline in kidney function in the chronic glomerulonephritis patients 31 , and with end stage renal disease attributed to hypertension 32 . In addition, EDN1 genetic variability was related to microvascular complications of T2DM such as diabetic retinopathy 33 , and DN 34 .…”