Abstract-There is accumulating evidence that endothelin-1 plays an important role in vascular pathophysiology. Our objective was to examine whether molecular variations at the endothelin-1 locus were involved in susceptibility to myocardial infarction and variation in blood pressure. The entire coding sequence and 1.4 kb of the 5Ј flanking region were screened. Five polymorphisms were detected, which were genotyped in the ECTIM (Etude Cas-Témoin de l'Infarctus du Myocarde) Study, a multicenter study comparing 648 male patients who had survived a myocardial infarction and 760 population-based controls. The polymorphisms were not associated with myocardial infarction, nor did they contribute to blood pressure levels in the population at large. However, a G/T polymorphism predicting an Lys/Asn change (ET1/C198) strongly interacted (PϽ0.001) with body mass index in the determination of blood pressure levels. There was a steeper increase of blood pressure with body mass index in carriers of the T allele than in GG homozygotes. As a consequence, the T allele was associated with an increase of blood pressure in overweight subjects (body mass index Ն26 kg/m 2 ), while no significant effect was observed in lean subjects (body mass index Ͻ26 kg/m 2 ). To determine whether this finding could be replicated, the ET1/C198 was genotyped in the Glasgow Heart Scan Study, a population-based study including 619 men and 663 women. Subjects homozygous for the T allele had higher resting blood pressure levels than others (PϽ0.05). A similar interaction between the T allele and body mass index was observed on the maximum blood pressure achieved during a treadmill exercise test (PϽ0.001). In conclusion, results from 2 independent studies suggest that the ET1/C198 polymorphism is associated with blood pressure levels in overweight people. (Hypertension. 1999;33:1169-1174.) Key Words: genes Ⅲ endothelin Ⅲ myocardial infarction Ⅲ hypertension, genetic Ⅲ blood pressure Ⅲ body mass index Ⅲ obesity E ndothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced by endothelial and smooth muscle cells. 1 It is found in a variety of tissues, where it acts as a modulator of vasomotor tone, cell proliferation, and hormone production (see References 2 and 3 for reviews). There is accumulating evidence from experimental and clinical data that ET-1 plays an important role in the pathophysiology of the vascular system. 3 ET-1 expression is enhanced in atherosclerosis and coronary endothelial dysfunction 4 -6 and may contribute to the rupture of active atherosclerotic plaques, leading to acute ischemic events. 7,8 Raised circulating concentrations of ET-1 have been observed in the acute phase of myocardial infarction (MI) 9 -11 and were related to an unfavorable prognosis after MI. 12 Congestive heart failure is also commonly associated with high ET-1 concentrations, 13-15 and long-term treatment with an endothelin-receptor antagonist has been reported to improve the survival of rats with chronic heart failure. 16 Because of its vasoconstrictor an...

Two strategies involving whole-genome association studies have been proposed for the identification of genes involved in complex diseases. The first one seeks to characterize all common variants of human genes and to test their association with disease. The second one seeks to develop dense maps of single-nucleotide polymorphisms (SNPs) and to detect susceptibility genes through linkage disequilibrium. We performed a molecular screening of the coding and/or flanking regions of 36 candidate genes for cardiovascular diseases. All polymorphisms identified by this screening were further genotyped in 750 subjects of European descent. In the whole set of genes, the lengths explored spanned 53.8 kb in the 5' regions, 68.4 kb in exonic regions, and 13 kb in the 3' regions. The strength of linkage disequilibrium within candidate regions suggests that genomewide maps of SNPs might be efficient ways to identify new disease-susceptibility genes, provided that the maps are sufficiently dense. However, the relatively large number of polymorphisms within coding and regulatory regions of candidate genes raises the possibility that several of them might be functional and that the pattern of genotype-phenotype association might be more complex than initially envisaged, as actually has been observed in some well-characterized genes. These results argue in favor of both genomewide association studies and detailed studies of the overall sequence variation of candidate genes, as complementary approaches.