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...

Background eQTL analyses are important to improve the understanding of genetic association results. Here, we performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results In a genome-wide association analysis of 2,078 CAD cases and 2,953 controls, we identified 950 single nucleotide polymorphisms (SNPs) that were associated with CAD at P<10-3. Subsequent in silico and wet-lab replication stages and a final meta-analysis of 21,428 CAD cases and 38,361 controls revealed a novel association signal at chromosome 10q23.31 within the LIPA (Lysosomal Acid Lipase A) gene (P=3.7×10-8; OR 1.1; 95% CI: 1.07-1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1,494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10-96). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10-3). Conclusions The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which itself was related to endothelial dysfunction, a precursor of CAD.