Genetic polymorphisms and haplotypes of eNOS in breast cancer

Abstract

To the Editor Recent studies published in this journal have shown contradictions regarding the possible association between polymorphisms of endothelial nitric oxide synthase (eNOS) gene and susceptibility to breast cancer [1–3]. While one study showed increased risk for breast cancer in subjects with the Asp allele for the Glu298Asp eNOS polymorphism [3], two other studies showed no significant association [1, 2]. Moreover, Lee and colleagues showed that eNOS haplotypes involving two eNOS polymorphisms (Glu298Asp in exon 7 and T-786C in the promoter region) were not associated with increased susceptibility to breast cancer [1]. However, these authors have not examined the influence of another important eNOS polymorphism in intron 4 (a variable number of tandem repeats), and maybe have missed important information. One major reason for such contradictions is that significant interethnic differences exist in the distribution of eNOS genotypes or haplotypes [4, 5]. However, haplotype (or diplotype) analysis can provide much more relevant biological information than the analysis of single polymorphisms, one by one. Indeed, the analysis of haplotypes may provide improved biological information in genetic association studies than the analysis of single polymorphisms [6]. For example, while single eNOS polymorphisms were not associated with increased susceptibility to another complex disease (hypertension), eNOS haplotypes involving three relevant eNOS polymorphisms were significantly associated with the development of hypertension [7–9]. These haplotype findings would have been missed if specific eNOS genotypes alone had been considered [7–9]. Importantly, the same specific eNOS haplotypes were associated with susceptibility to hypertension in subjects with different ethnic backgrounds [7–9], even though significant interethnic differences exist in the distribution of eNOS genotypes or haplotypes [4, 5]. Therefore genetic markers were much more important that ethnicity. We believe that the best way to avoid contradictions is to carry out studies based on the analysis of eNOS haplotypes involving all relevant polymorphisms. This approach will probably reveal which eNOS haplotypes, if any, are really associated with increased susceptibility to breast cancer.