Endothelial Nitric Oxide Synthase Polymorphisms and Susceptibility to Hypertension: Genotype Versus Haplotype Analysis
To the Editor:
Zintzaras et al reported interesting results of a meta-analysis of all the available studies on the possible association between endothelial NO synthase (eNOS) polymorphisms and hypertension.1 They concluded that there is evidence for significant association between the 4b/4a variable number of tandem repeats polymorphism in intron 4 of the eNOS gene and susceptibility to hypertension, without significant influence for other eNOS polymorphisms.1
Although meta-analysis may shed some light on contradictory results derived from a number of different case-control studies, we believe that haplotype (or diplotype) analysis can provide more relevant biological information. In fact, the analysis of haplotypes (specific combinations of genetic markers within a chromosome cluster location) has been valued as a more powerful approach in association studies than the analysis of single polymorphisms. For example, we have recently reported that eNOS haplotypes involving 3 of the most studied eNOS polymorphisms are associated with the development of hypertension.2,3 Interestingly, single eNOS polymorphisms were not associated with hypertension in these studies. Therefore, our haplotype findings would have been missed if specific eNOS genotypes alone had been considered.2,3 Importantly, we found that the same specific eNOS haplotypes are associated with susceptibility to hypertension in subjects with different ethnic backgrounds,3 even though significant interethnic differences exist in the distribution of eNOS genotypes or haplotypes.4,5 Our results support the suggestion that significant interactions between individual eNOS polymorphisms play a role in the genetic susceptibility to hypertension, but not individual eNOS polymorphisms. This conclusion would hardly be drawn with a meta-analysis based on single polymorphism studies, as the one conducted by Zintzaras et al. We believe that a meta-analysis based on eNOS haplotypes can lead to more reliable conclusions than that based on eNOS genotypes.
Zintzaras E, Kitsios G, Stefanidis I. Endothelial NO synthase gene polymorphisms and hypertension. A meta-analysis. Hypertension. 2006; 48: 700–710.
Marroni AS, Metzger IF, Souza-Costa DC, Nagassaki S, Sandrim VC, Correa RX, Rios-Santos F, Tanus-Santos JE. Consistent interethnic differences in the distribution of clinically relevant endothelial nitric oxide synthase (eNOS) genetic polymorphisms. Nitric Oxide. 2005; 12: 177–182.