Susceptibility-conferring polymorphic genotypes in cardiovascular multifactorial syndromes.

In 2001, the search for gene polymorphism has become a popular challenge in every cardiovascular journal and congress, particularly concerning hypertension and myocardial infarction. These studies were aimed at detecting markers for drug efficacy and risk factors and more generally at better understanding the determinants of these complex diseases that are both multifactorial and multigenic. For the moment, however, such an approach induces more confusion than clarification. The best example of such confusion is the endless debate around the linkage with an Insertion, I/Deletion, D, polymorphism DD/ID/II of the angiotensin converting enzyme, ACE, gene. The ID polymorphism is located in position 287 on the intron 16. It follows Mendelian laws and is in linkage disequilibrium with the gene locus involved in the control of plasma ACE levels. Several studies showed that the plasma levels of ACE were significantly lower in II genotype than in DD. Since the pioneer work of F. Cambien, conflicting data regarding the association between this polymorphism and myocardial infarction have been reported almost monthly. Currently 12 articles support the association, and five, including a large meta-analysis, found no or little influence from the different genotypes. In addition, unsuccessful attempts were made by several authors to correlate this polymorphism with hypertension, restenosis or drug effects. The story is roughly the same for the two integrins, and also for other polymorphisms located on endothelial NO synthase, paraoxonase-1, aldosynthase, plasminogen activator inhibitor-1 genes, and probably several others. The search for a candidate gene in hypertension is still more depressing. The Gly460Trp polymorphism, located on ADDA, the -adducin gene, is a functional polymorphism linked to hypertension in several studies, while others were unable to confirm the linkage. Attempts to link hypertension with several functional polymorphisms of the adrenergic system, including the Gly16 variant of the 2-receptor (which exhibited enhanced isoproterenol-induced down-regulation), the 825T allele of the 3-subunit of the G-protein (which is associated with enhanced signal transduction) also resulted in pros and cons in equal measure. Two candidates have been studied in depth, the angiotensinogen, and epithelial amiloride-sensitive sodium channel (ENaC) genes. It is now clear that the 235T variant of angiotensinogen is in linkage disequilibrium with an A-6C functional variant located on the promoter of angiotensinogen. See page 325, doi:10.1053/euhj.2001.2776 for the article to which this Editorial refers