Do meta-analyses of association studies of endothelial nitric oxide synthase variants and ischemic heart disease provide conclusive answers?

Abstract

To the Editor: A meta-analysis suggested that the Asp298 (894T) and an intron-4 single-nucleotide polymorphism (SNP), but not the promoter −786C allele, in the endothelial NO synthase (eNOS) gene would increase the risk of ischemic heart disease (IHD).1 Although based on studies of >23 000 subjects, this conclusion is amazing. The authors stated an increased susceptibility to cleavage of the Asp298-encoded eNOS enzyme,1 but this was disproved.2 Thus, no evidence for a functional role of these SNPs exists. In contrast, the −786C allele bears functional consequences, because it creates a binding site for a RPA-1 protein that blunts transcription3; it is also in linkage disequilibrium and interacts with the Asp298 in causing endothelial dysfunction.3 Serendipity or linkage disequilibrium with functional variants, as the −786C allele, in the eNOS and/or other genes might therefore explain the association of these SNPs with IHD.1 The meta-analysis was underpowered to detect an association of the −786C allele with IHD, because of the few available studies.1 Regrettably, two large studies that reported an association of this SNP with coronary artery …