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 locat ed 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 converti ng 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 li nkage disequilibrium with an unidentified functional variant which wou ld affect the regulation of the gene in response to angiotensin II. Th e present study was conducted to identify new polymorphisms of the AT( 1)R gene that might be responsible for this interaction. Methods The f irst 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 dete cted in the 5' region at positions -1424, -810, -713, -521, -214, -213 and -153 upstream from the start of transcription. The genotypes of t he -810, -713, -214, -213 and -153 polymorphisms were completely conco rdant. One substitution was detected at the 55th nucleotide of exon 4, These polymorphisms, together with the +1166 A/C polymorphism and a p reviously described T/C substitution at the 573th nucleotide of exon 5 , were genotyped in the Etude Cas-Temoin de l'Infarctus du Myocarde (E CTIM) study, a multicentre study comparing 651 patients who had surviv ed a myocardial infarction and 728 controls from Belfast (United Kingd om) and Lille, Strasbourg and Toulouse (France). Results The newly ide ntified polymorphisms were not in linkage disequilibrium with the +116 6 A/C polymorphism and therefore could not explain the interaction obs erved with ACE I/D. None of the polymorphisms was associated with bloo d pressure levels in control subjects. In the four populations, the A allele of the -810 polymorphism was associated with a lower risk of my ocardial infarction (population-adjusted odds ratio of 0.80, confidenc e interval 0.65-0.97, P < 0.05). Conclusions None of the newly identif ied polymorphisms could account for the previously described interacti on between the AT(1)R+1166 A/C and the ACE I/D polymorphisms affecting the risk of myocardial infarction. However, the present study suggest s that AT(1)R-810 T/A, or other polymorphisms which are in complete as sociation with it, might be associated with the risk of myocardial inf arction. Further studies are required to confirm this finding and to i dentify the functional variants. (C) 1998 Lippincott Williams & Wilkin s.