A MISSENSE GLU298ASP VARIANT IN THE ENDOTHELIAL NITRIC-OXIDE SYNTHASEGENE IS ASSOCIATED WITH CORONARY SPASM IN THE JAPANESE

Coronary spasm plays an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general. However, t he precise mechanism(s) by which coronary spasm occurs remains to be e lucidated. Coronary spasm may arise from interactions between environm ental and genetic factors. Endothelial-derived nitric oxide (NO) has b een implicated in the control of vascular tone. We have recently shown that both basal and acetylcholine (ACh)-induced NO activities are imp aired in the coronary arteries of patients with coronary spasm. The pu rpose of this study has been to elucidate the possible variants that o ccur in the coding region of the endothelial nitric oxide synthase (eN OS) gene and that may be associated with coronary spasm. After initial screening in the entire 26 coding regions of the eNOS gene, we found a missense Glu298Asp variant in exon 7 in patients with coronary spasm . We subsequently performed a larger scale study involving 113 patient s with coronary spasm and 100 control subjects, who were all diagnosed by intracoronary injection of ACh. The analysis revealed a significan t difference in the distribution of the variant between the coronary s pasm group (21.2%) and control group (9.0%; P = 0.014 for dominant eff ect). Thus, we have found the missense Glu298Asp variant in the eNOS g ene by the analysis of its entire 26 coding regions. The variant is si gnificantly associated with coronary spasm.