New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTIM study

Objective In an earlier report, we suggested that a polymorphism located in the 3' untranslated region of the angiotensin II type 1 receptor gene (AT(1)R+1166 A/C) might interact with the angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism to increase the risk of myocardial infarction. Since the AT(1)R+1166 A/C polymorphism does not appear to be functional, we postulated that it might be in linkage disequilibrium with an unidentified functional variant which would affect the regulation of the gene in response to angiotensin II. The present study was conducted to identify new polymorphisms of the AT(1)R gene that might be responsible for this interaction. Methods The first four exons, which are untranslated, and 2.2 kb in the 5' flanking region of the AT(1)R gene were explored by polymerase chain reaction/single-strand conformation polymorphism. Seven polymorphisms were detected in the 5' region at positions -1424, -810, -713, -521, -214, -213 and -153 upstream from the start of transcription. The genotypes of the -810, -713, -214, -213 and -153 polymorphisms were completely concordant. One substitution was detected at the 55th nucleotide of exon 4, These polymorphisms, together with the +1166 A/C polymorphism and a previously described T/C substitution at the 573th nucleotide of exon 5, were genotyped in the Etude Cas-Temoin de l'Infarctus du Myocarde (ECTIM) study, a multicentre study comparing 651 patients who had survived a myocardial infarction and 728 controls from Belfast (United Kingdom) and Lille, Strasbourg and Toulouse (France). Results The newly identified polymorphisms were not in linkage disequilibrium with the +1166 A/C polymorphism and therefore could not explain the interaction observed with ACE I/D. None of the polymorphisms was associated with blood pressure levels in control subjects. In the four populations, the A allele of the -810 polymorphism was associated with a lower risk of myocardial infarction (population-adjusted odds ratio of 0.80, confidence interval 0.65-0.97, P < 0.05). Conclusions None of the newly identified polymorphisms could account for the previously described interaction between the AT(1)R+1166 A/C and the ACE I/D polymorphisms affecting the risk of myocardial infarction. However, the present study suggests that AT(1)R-810 T/A, or other polymorphisms which are in complete association with it, might be associated with the risk of myocardial infarction. Further studies are required to confirm this finding and to identify the functional variants. (C) 1998 Lippincott Williams & Wilkins.