Abstract-Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced by endothelial and smooth muscle cells.Many lines of biological evidence suggest that the ET-1 gene is a candidate gene for hypertension. Moreover, recent association studies suggested that a G/T polymorphism with an amino acid substitution (Lys/Asn) at codon 198 in exon 5 of the ET-1 gene interacts with body mass index (BMI) in association with blood pressure. They suggested that T carriers are more sensitive to weight gain than GG homozygotes in association with blood pressure. However, association studies are often irreproducible, and the first study often suggests a stronger genetic effect than is found by subsequent studies. We therefore assessed the interaction in 2 large Japanese populations. The present study showed a nonsignificant but similar trend to the results of previous reports. Moreover, in line with previous reports, this study revealed a significant interaction between the ET-1 K198N (G/T) polymorphism and BMI in association with hypertension in our populations (Pϭ0.027). The interaction was significant, even after adjustment for gender and age (Pϭ0.045) and for all confounding factors (Pϭ0.044). T carriers were more sensitive to weight gain than GG homozygotes in association with hypertension. Considering the combined impact of obesity and hypertension on the development of cardiovascular and cerebrovascular disorders, T allele carriers might represent elective targets for therapy to lower their body weight. Key Words: endothelin Ⅲ hypertension, essential Ⅲ genetics Ⅲ polymorphism Ⅲ body mass index E ndothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced by vascular endothelial cells. 1 Some patients with moderate-to-severe essential hypertension, similar to some experimental rat models with severe blood pressure elevation, exhibit enhanced endothelial expression of the ET-1 gene. 2 Plasma ET-1 concentration is elevated in hypertensive patients. 3-6 An endothelin-receptor antagonist significantly lowered blood pressure in patients with essential hypertension. 7 Given these lines of biological evidence, the ET-1 gene is a candidate responsible for hypertension.Hypertension is a common, complex phenotype and has been intensively studied to identify susceptibility loci in humans. Nonetheless, there is no known genotypic polymorphism consistently associated with hypertension in humans, thus far. Moreover, albeit that the development of hypertension is considered to be due at least partly to gene-gene and gene-environmental interactions, fewer interaction analyses have been conducted than simple association analyses. In this regard, the ET-1 gene is an attractive candidate because, in addition to its biological function, this gene has been shown to interact with body mass index (BMI) in association with blood pressure in 3 large populations. 8,9 However, association studies are often irreproducible, and the first study often suggests a stronger genetic effect than is found by subsequent studies. 10 We therefore a...

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hypertension (2-4), an initial study examined the association between a common silent polymorphism (T393C) in GNAS1 and hypertension (5). This study showed that the T393C polymorphism was significantly associated with hypertension and with poor responsiveness to β-blockade. Subsequently, we also studied the association in a large Japanese population, resulting in replication of the association between the T393C polymorphism and hypertension (6). Additionally, in the same population, we showed that the T393C polymorphism interacted with cigarette smoking and with al-

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