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CLINICAL STUDY: POLYMORPHISMS AND CARDIOVASCULAR DISEASE

The T^-786C endothelial nitric oxide synthase genotype is a novel risk factor for coronary artery disease in Caucasian patients of the GENICA study

Gian Paolo Rossi, MD, FACC, FAHA^,*, Maurizio Cesari, MD, Mario Zanchetta, MD^*, Stefania Colonna, MD, Giuseppe Maiolino, MD, Luigi Pedon, MD^*, Martina Cavallin, BiolD, Pietro Maiolino, MD^* and Achille C. Pessina, MD, PhD

^* Servizio di Emodinamica and Divisione di Cardiologia Ospedale di Cittadella, University of Padova, Padova, Italy
Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Padova, Italy

Manuscript received March 13, 2002; revised manuscript received October 7, 2002, accepted November 22, 2002.

^* Reprint requests and correspondence: Prof. Gian Paolo Rossi, Department of Clinical and Experimental Medicine, Clinica Medica 4 University Hospital, via Giustiniani, 2, 35126 Padova, Italy.
gianpaolo.rossi{at}unipd.it

OBJECTIVES: We investigated the association of polymorphisms in the promoter region and exon 7 endothelial nitric oxide synthase (eNOS) gene with coronary artery disease (CAD).

BACKGROUND: Endothelial dysfunction foretells cardiovascular events and can be genetically determined.

METHODS: We genotyped for the promoter (T^-786C) and exon 7 (Glu298Asp, G⁸⁹⁴T) polymorphisms in 1,225 subjects; 1,106 were consecutive patients undergoing coronary angiography and 119 control subjects without any cardiovascular risk factors. Genotyping was performed with melting curve analysis of polymerase chain reaction products from allele-specific acceptor and donor probes that were 5'- and 3'-end labeled with LCRed640 and fluorescein, respectively; CAD was assessed by quantitative coronary angiography. We performed multiple logistic regression analysis for the effect of the T^-786C, the missense Glu298Asp variant, and other coronary risk factors on two- and three-vessel CAD.

RESULTS: The overall genotype distribution of T^-786C (CC = 17.7%, CT = 40.4%, and TT = 41.9%) and Glu298Asp (GG = 43.3%, GT = 37.0%, and TT = 19.7%) was consistent with the Hardy-Weinberg equilibrium. The regression analysis showed that the T^-786C, but not the missense Glu298Asp variant, significantly predicted CAD, independent of other risk factors. Compared with TT homozygous, subjects carrying the C allele had a significant (p = 0.002) increase in the odds ratio of harboring two- or three-vessel CAD of 1.672 (95% confidence interval, 1.062 to 2.527). A subgroup analysis confirmed this effect of the T^-786C polymorphism in men (p = 0.007), cigarette smokers (p = 0.001), subjects older than 60 years of age (p = 0.007), with hypercholesterolemia (p = 0.011), low high-density lipoprotein cholesterol (p = 0.006), and overweight or with obesity (p = 0.041).

CONCLUSIONS: The C allele at the T^-786C endothelial nitric oxide synthase polymorphism is associated with a higher risk of multivessel CAD in Caucasians.

Abbreviations and Acronyms   CAD   coronary artery disease   CV   cardiovascular   eNOS   endothelial nitric oxide synthase   GENICA   Genetic and ENvironmental Factors in Coronary Atherosclerosis study   HDL   high-density lipoprotein   LDL   low-density lipoprotein   MI   myocardial infarction   NO   nitric oxide

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