Endothelial Nitric Oxide Synthase (eNOS) Polymorphism

What Is eNOS

Nitric oxide (NO) is a major mediator of endothelium-dependent vasodilatation. It is made in endothelial cells from L-arginine through the action of the homodimeric enzyme exdothelial nitric oxide synthase (eNOS).

Pathophysiology/Clinical Significance

The eNOS gene is expressionally and functionally regulated through multiple regulator steps, and entails several polymorphisms, some of which bear functional consequences. There are three clinically relevant eNOS polymorphisms: T786C in the promoter, the variable number of tandem repeats (VNTR) in intron 4, and the Glu298Asp variant in exon 7.The T786C is the most important for the regulation of transcription rate of the eNOS gene. This polymorphisms were found to be associated with an altered coronary vasomotor reactivity and with an impaired endothelium-dependent vasodilatation.

In a study of Caucasian hypertensive patients, the genotype distribution of T -786C (CC [normal] = 21.9%, CT [heterozygote] = 48.7%, TT [homozygote] = 29.4%) and Glu298Asp (GG = 39.0%, GT =51.9%, TT = 9.1%) was similar in hypertensive and normotensive subjects. A significant effect of the T -786C (p = 0.002) but not of the Glu298Asp (p = NS) eNOS polymorphism on endothelial-dependent vasodilatation was found. In addition, the T786C, but not the Glu298Asp polymorphism, significantly predicted coronary artery disease in Caucasians. The T786C polymorphism was also found to reduce promoter activity and predispose to coronary spasm in a Japanese population.

Populational Distribution

There was a notable disparity in the distribution of three clinically relevant eNOS polymorphisms (T786C; Intron4; Glu298Asp) among three ethnic groups (Caucasians-Cc; African-American-Aa; Asians-As). The T786C variant was more common in Cc (42%) than in Aa (17.5%) or As (13.8%). Similarly, the Glu298Asp variant was also more common in Cc (34.5%) than in Aa (15.5%) or As (8.6%). Correspondingly, the heterozygote or homozygote variant genotypes for both T786C and Glu298Asp polymorphisms were more common in Cc than in the other two ethnic groups. On the other hand, the intron4 variant was more common in As (26.5%) than in Cc (16.0%) or As (12.9%).

References

1. Yoshimura M, Nakayama M, Shimasaki Y, Ogawa H, Kugiyama K, Nakamura S, Ito T, Mizuno Y, Harada E, Yasue H, Miyamoto Y, Saito Y, Nakao K. A T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene and coronary arterial vasomotility. Am J Cardiol. 2000 Mar 15;85(6):710-4.
2. Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H, Motoyama T, Saito Y, Ogawa Y, Miyamoto Y, Nakao K. T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation. 1999 Jun 8;99(22):2864-70.
3. Hibi K, Ishigami T, Tamura K, Mizushima S, Nyui N, Fujita T, Ochiai H, Kosuge M, Watanabe Y, Yoshii Y, Kihara M, Kimura K, Ishii M, Umemura S. Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension. 1998 Sep;32(3):521-6.
4. Tanus-Santos JE, Desai M, Flockhart DA. Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics. 2001 Nov;11(8):719-25.
5. Rossi GP, Taddei S, Virdis A, Cavallin M, Ghiadoni L, Favilla S, Versari D, Sudano I, Pessina AC, Salvetti A. The T -786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol. 2003 Mar 19;41(6):938-45.
6. Rossi GP, Cesari M, Zanchetta M, Colonna S, Maiolino G, Pedon L, Cavallin M, Maiolino P, Pessina AC . The T-786C endothelial nitric oxide synthase genotype is a novel risk factor for coronary artery disease in Caucasian patients of the GENICA study. J Am Coll Cardiol. 2003 Mar 19;41(6):930-7.