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

a total of 17 articles with 2631PAH subjects and 5139 controls and 5 candidate gene variants that also included rs5370 SNP of EDN1 gene for susceptibility to PAH showed a significant association between "T" allele carriers and risk of developing PAH [54]. Another large-scale genomic analysis to examine the interaction of ET-1 pathway polymorphisms and treatment response of patients with PAH treated with ET receptor anatagonists (ERAs) showed that these polymorphisms of the ET-1 pathway may influence the clinical efficacy of ERAs [55].

## **7.2 Essential hypertension**

There are several reports connecting this SNP variant to hypertension. Our own studies (unpublished) like those of Wiltshire et al. [43] have found no sufficient data supporting the association between K198N polymorphism with high blood pressure, systolic blood pressure, lipid levels, and insulin resistance or metabolic syndrome. In other studies, subjects with high endothelin-1 levels were shown to have an increased risk of low-renin hypertension [56]. Rs5370 variant of EDN1 has been associated with low-renin hypertension and increased aldosterone/renin ratios in individuals of African descent, but not in whites [57]. This study also provided the first evidence of a potential association between the *EDN1* rs5370 SNP and the risk of subclinical hyperaldosteronism in subjects of African descent. These investigators also assessed the effect of EDN1 rs5370 on systolic BP curves, but they did not see an effect. They also observed a significant association of salt-sensitive BP and rs5370, even with adjustment for sex, since an earlier study [58] had reported sex differences in the relationship between systolic BP and a haplotype of *EDN1.* In rheumatoid arthritis, hypertension is quite common and has been reported to be associated with the endothelin-1 (ET-1) gene locus (EDN1) in some groups, such as the Afro-Caribbean but not in the general population. Some other groups where hypertension-related high levels of plasma ET-1 in RA have been observed are the obese and individuals with low-renin states. A study [59] that evaluated the potential association of EDN1 gene locus and serum ET-1 levels with hypertension in patients with RA showed an increase in the prevalence of T-T haplotype carriers.

## **7.3 Preeclampsia**

Preeclampsia (PE) is an often-fatal pathology characterized by hypertension and proteinuria at the 20th week of gestation that affects 5–10% of the pregnancies [46]. Risk factors for the development of PE include obesity, insulin resistance, and hyperlipidemia that stimulate inflammatory cytokine release and oxidative stress leading to endothelial dysfunction (ED). Normal pregnancy course includes variations in hemodynamics, in which placenta allows the exchange of nutrients and waste disposal between mother and fetus. During the stage of establishment of maternal-fetal interface when the extravillous throphoblasts from placenta conquer the maternal decidua, the maternal spiral arteries from the decidua go through a process of remodeling, where they are upgraded from low-capacity high-resistance into high-capacity low-resistance vessels. PE is characterized by an impaired invasion of fetal trophoblasts which causes a reduced remodeling of the maternal spiral arteries eventually leading to a decrease in blood flow to the placenta. Consequently, the mother develops hypertension, usually at the end of the second or third trimester of

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

gestation, to increase the blood flow. The polymorphism rs5370 in EDN1 was shown to be associated with susceptibility to preeclampsia [60]. In another study [61], markedly increased risk of early onset of PE was shown to be related to the C allele polymorphism rs5370 in *EDN1.*

## **7.4 Glaucoma**

ET-1 has been suggested to have a role to play in optic neuropathy observed in glaucoma [62]. Associations between polymorphisms of endothelin (ET-1) and endothelin receptors (ER) A and B genes with the occurrence of glaucoma were investigated by Ishikawa et al. [63] in Japanese patients. For the rs5370 ET-1 polymorphism that involved a transversion of G/T in exon 5, the Lys-Lys (GG) genotype tended to be more frequent than in open-angle glaucoma patients.

## **7.5 Diabetic retinopathy (DR)**

Diabetic retinopathy (DR) is the result of impaired NO pathway that affects the vusculature of the retina. Several candidate genes have been studied for their role in diabetic retinopathy, but only a fraction of them have been shown to be associated with DR. Many studies have provided evidence in support of the role of endothelin (ET) system in the pathophysiology of DN. However, studies on K198N variant have revealed that the "T" (Asn) allele actually has a protective role against DR in a Chinese population with type 2 diabetes [64]. Yet another study by Maja Seruga [65] showed that the EDN1 rs5370, rs1476046, and rs3087459 polymorphisms of EDN1 gene are not risk factors for DN in Caucasians with T2DM.

## **7.6 Childhood primary nephrotic syndrome**

ET-1 levels are raised in children with first episode of nephrotic syndrome (FENS), pointing toward endothelial dysfunction [66]. Also, children with steroid resistance have a greater risk of endothelial dysfunction [67]. The rs5730 SNP of EDN1 gene might play a disease-modifying role and susceptibility to childhood primary nephrotic syndrome (CPNS) [68]. Plasma Cholesterol, a hallmark of NS, seems to be associated with the genetic variations within the human ET-1 gene. The other EDN1 SNPs associated with CPNS include rs1630736 and rs10478694 (3A/4A) and rs9296344 [69]. In a case-control study, it was found that GG genotype was more frequent in steroid-sensitive NS group compared to the steroidresistant NS group and was associated with hypertension. This group also showed a better response to steroid therapy [70]. The study by Hashemi et al. [71], however, did not find any association of rs5370 G > T variant with nephrotic syndrome in children.
