**7. Endothelin-1 gene polymorphism**

An individual's phenotypic characteristics, including a person's propensity toward complex disorders such as heart disease and cancer at the genetic level, are determined by sequence variations that exist at defined positions within genomes. Sequence variations are tools for understanding human variation and molecular genetics and can be used for gene mapping, definition of population structure, and performance of functional studies. The human genome has a total of over 88 million variants of which 84.7 million are SNPs, 3.6 million short insertions/deletions (indels), and 60,000 structural variants (The 1000 Genomes Project Consortium, Nature, 2015 [8]). A typical genome differs from the reference human genome at 4.1million−5.0 million sites. Realizing the importance of the role of SNPs in human health, many databases like Ensembl Variation Database, A-SNP, HGBase (Human Genic Bi-allelic SEquences), HOWDY (Human organized whole-genome variation Database), and dbSNP have been created for cataloging the variations occurring in human genome. The emergence of genetic variation databases, such as (i) dbSNP and HGV for short genetic variations, (ii) dbVar and DGV for structural variations, (iii) dbGaP for genotype/phenotype interaction studies, and (iv) ClinVar and ClinGen for human variations of clinical significance, facilitates the contemporary identification/discovery of (i) known or novel polymorphisms, (ii) phenotype to genotype associations, and (iii) clinically important human genetic variations.

The Single Nucleotide Polymorphism Database (dbSNP) is **a free public archive for genetic variation** developed and hosted by the National Centre for Biotechnology Information (NCBI) in collaboration with the National Human Genome Research Institute (NHGRI). This collection of polymorphisms includes


Majority of the genetic variations among individuals are due to SNPs. The association of candidate gene SNPs like those of EDN1 in multifactorial diseases, like endothelial dysfunction which often set the stage for the occurrence of vascular diseases like CAD, is important for the identification of therapeutic targets.

The gene for ET-1 gene locus spans a region of approx. 7.0 kb on short arm of chromosome 6 at 6p24–23 [49, 50]. The gene is composed of five exons (**Figure 3**) that synthesizes a cDNA of 2026 bps. Nucleotide sequences encoding the mature ET-1 are present in the second exon. ExonI has the 5'UTR of mRNA. The upstream promoter region is well conserved.

The endothelin pathway is central to pulmonary vascular function. Several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. The dbSNP contains 15,259 entries for human *EDN1* gene (as on 20.06.2022) which represent

*An Overview of Gene Variants of Endothelin-1: A Critical Regulator of Endothelial Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.108108*

#### **Figure 3.**

*EDN1 Gene Locus and some of its common gene variants. The EDN1 gene is located on short arm (p-arm) of chromosome 6 and has five exons (green), a 5'non-translated region and a 3'non-translated region of the gene that is transcribed in mRNA. The 5'ntr is located downstream of promoter, while the 3'ntr is located downstream of exon 5. The gray areas of the gene represent the introns that are spliced off in the mature RNA. The rs nos. of commonly studied SNP variants in EDN1 gene are mentioned in blue horizontal bars in extreme right. The complete data from SNPs build 155 are available at https://ftp.ncbi.nlm.nih.gov/snp/ in multiple formats.*

all the above categories of variations. Many of these entries are redundant. For example, rs386556298, rs60458956, rs56478068, and rs3730357 have been merged into rs2070699 which represents intron variant c.233 + 30 G > C/G > T variation in the *EDN1* gene. A total of 15 of these as represented in the ClinVar database (Build 155, Jun 16, 2021) have been included in **Table 1** due to the limitation of space in this article.

This is by far the most reported variant of pre-proendothelin-1, and there are 161 publications (21.06.2022) in LitVar for this variant. The third base "**G"** of codon 198 of preproendothelin-1 gene is substituted with "**T"** leading to a change in codon for lysine to arginine. The genotypic variants of rs5370 are GG, GT, and TT. In the ECTIM (**Etude Cas-Témoin de l'Infarctus du Myocarde)** multicenter study [51] comprising of 648 male patients who had survived myocardial infarction and 760 population-based controls, the G/T polymorphism predicting the Lys/Asn change showed that the "T" allele was associated with increase of blood pressure in overweight subjects. This finding was confirmed by the Glasgow Heart Scan Study [51] as well.

#### **7.1 Pulmonary arterial hypertension**

Endothelial dysfunction is believed to be one of the first triggers initiating the process of abnormal vascular remodeling in pulmonary arterial hypertension (PAH) [52]. K198N (rs5370) polymorphism in the endothelin 1 gene (EDN1) has been demonstrated to associate with blood pressure reactivity and can result in greater endothelin-1 (ET-1) synthesis which may favor the development of PAH and affect its course of progression [53]. The influence of EDN1 gene variants on susceptibility to pulmonary arterial hypertension remains uncertain. However, a meta-analysis of


*Endothelial Dysfunction - A Novel Paradigm*


*15 SNP variants reported in Clinvar database having pathophysiological significance are mentioned with their rs I'd, allelic variation, their occurrence in coding vs. noncoding region in the gene, their coordinates, and 25 nucleotide upstream and the downstream flanking sequences and the amino acid change associated with SNPs in the exonic/coding region. SNPs mentioned here are from transcript variant 1 (NM\_001955.5) and the corresponding genomic RefSeq EDN1 gene (NG\_016196.1). Among 15 SNPs, 5 are benign, 3 are likely benign, 3 are of uncertain significance, and 4 are pathogenic. One of the SNP rs5370 G > T has multiple submitters. The complete data from SNPs build 155 are available at https://ftp.ncbi.nlm.nih. gov/snp/ in multiple formats.*
