Analysis of Heritable Components of Primary Nocturnal Enuresis: Relevance of Haplotypes Instead of Genotypes
To the Editor,
Balat and colleagues reported interesting findings related to the possible association between neuronal (nNOS) and endothelial (eNOS) nitric oxide synthase gene polymorphisms and primary nocturnal enuresis in Turkish children.Citation[1] While the glu298asp (G/T) polymorphism of eNOS gene was not associated with nocturnal enuresis, a significant association was found between this common disorder and the polymorphism of the nNOS gene.Citation[1] Although their findings are potentially of great clinical relevance, we are a little skeptical about their negative findings, which rule out a possible eNOS-related heritable contribution to nocturnal enuresis. Balat and colleagues could have genotyped for a few additional clinically relevant eNOS gene polymorphisms and carried out a haplotype analysis. It has been widely acknowledged that haplotype (i.e., a combination of genetic markers within a chromosome cluster location) analysis can provide much more relevant biological information and is a more powerful approach in genetic association studies than the analysis of single polymorphisms.Citation[2] For example, recent studies have shown that eNOS haplotypes involving the most studied eNOS polymorphisms are associated with the development of hypertension.Citation[3–5] Interestingly, single eNOS polymorphisms were not associated with hypertension in these studies. Therefore, haplotype findings would have been missed if specific eNOS genotypes alone had been considered.Citation[3–5] Also of note, the same specific eNOS haplotypes were associated with susceptibility to hypertension in subjects with different ethnic backgrounds,Citation[3–5] even though significant interethnic differences exist in the distribution of eNOS genotypes or haplotypes.Citation[6],Citation[7] These findings support the notion that interactions between NOS polymorphisms may be part of the heritable components of some complex conditions, as it is the case of primary nocturnal enuresis. Such a conclusion would be obscured if specific polymorphisms alone had been considered.
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