**7.7 Asthma**

EDN1 has been reported to be implicated in the pathophysiology of asthma. In a study on 342 families from UK and 100 families from Norway, rs5370 along with 10 other EDN1 variants rs1800541, rs1800542, rs1476046, rs1800543, rs5369, rs1794849, rs1626492, rs1629862, rs1630736, and rs4714383 were genotyped, and a strong association was found in both the populations for rs5370 and rs1800541 located in

the upstream region of EDN1 gene [72]. However, literature results on the genetic association of EDN1 in asthma are inconsistent.

## **7.8 As risk predictors in cancer**

Ma et al. analyzed the genotypes of angiogenesis-related genes in 180 patients with nasopharyngeal carcinoma (NPC) using Sequenom MassARRAY and found that EDN1-rs1800541, rs2071942, and rs5370 can be used as risk predictors of radiationinduced oral mucositis, xerostomia, and myelosuppression, respectively.

Auriculocondylar Syndrome and Question Mark Ears.

rs587777231 [Lys91Glu].

rs587777232[Pro71His].

rs587777233[Val64Asp],

rs587777234 [Tyr81 Termination (stop gained)].

Auriculocondylar syndrome (ACS) is a rare disorder which affects facial development with a small chin micro-gnatha) and a malfunction of the joint that connects the lower jaw (mandible) to the skull—a condition referred to as mandibular hypoplasia. Another feature of this disorder is malformed outer ears that have a characteristic shape caused by a split that separates the upper ear from the earlobe (question-mark ears or QMEs). Ref. [73] identified a homozygous substitution in a furin cleavage site of the EDN1 proprotein in ACS-affected siblings born to consanguineous parents by whole-exome sequencing (WES). Four mutations (S.No. 11–14 in the ClinVar Table) were identified in the EDN1 gene, one of which resulted in a stop codon and the other three resulted in missense mutations. These mutations also had different modes of inheritance, suggesting that the degree of residual EDN1 activity differed depending on the mutation. These findings provided support for the hypothesis that ACS and QMEs are uniquely caused by disruption of the EDN1-EDNRA signaling pathway which is important in the development of the lower jaw. The four variants are classified in ClinVar database as pathogenic having clinical manifestations.

rs1800997: 3A/4A (+138 5'UTR locus of exon1 ins/del A) polymorphism. (Formerly rs10478694)

This SNP contains an adenine insertion at position +138, 5′ untranslated region (UTR) and exon 1 of the ET-1 [74]. The genotypes are as follows: the mutant form (4A/4A), wild type (3A/3A), and the heterozygote (3A/4A) [53]. Some studies have reported increased plasma levels of ET-1 in individuals who have a mutant genotype [53, 75]. Studies have reported different allele distributions among patients with pulmonary artery hypertension (PAH), idiopathic pulmonary artery hypertension (IPAH), and coronary heart disease (CHD), with the control group [76]. They showed a significant increase of alleles containing the 3A form in patients with hypertension [76]. Some researchers have shown that there is no significant association between this SNP and the development of hypertension [77]. This SNP, although, not reported in ClinVar database has been shown to be associated with high expression levels of ET-1 both in vitro (Popowski) and in vivo (Abhishek Kumar, 2021), and the high expression levels associated with the homozygous mutant form 4A/4A were hypothesized to be deleterious to cyanotic children with severe pulmonary hypertension [75].

Other variants not reported in ClinVar Database but reported in literature as heritable risk variants in many cardiovascular disorders such as hypertension, coronary artery disease, ventricular arrhythmia, and other related disorders are shown in **Figure 3**.

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