Progression of Atherosclerosis Is Associated With Variation in the 1-Antitrypsin Gene

Objective— 1-Antitrypsin (AAT) protects elastic tissue and may play a role in atherogenesis. The association of atherosclerosis progression with common AAT variants was considered in 2 clinical trials. Methods and Results—We examined the association of AAT V213A, S and Z deficiency alleles, and the functional 3 UTR 11478G A with change in minimal luminal diameter, a measure of focal disease, in the Lopid Coronary Angiography Trial gemfibrozil study of post-bypass men. S or Z carriers (n 14) showed strong progression of disease on placebo (11.5%) but responded well to treatment (3% regression). 11478A carriers treated with placebo or gemfibrozil showed significantly more disease progression (n 8, 14.5% and n 16, 4.0%, respectively) than 11478GG men (n 107, 7.0% and n 108, 1.4%, respectively; overall, P 0.003). VV213 men treated with gemfibrozil (n 68) showed 4.8% progression, whereas A213 carriers (n 55) showed 1.4% regression of disease (P 0.001). No V213A effect was seen on placebo (P 0.11). In the Diabetes Atherosclerosis Intervention Study fenofibrate trial of angiographic progression in type 2 diabetes, the association of 11478A with increased disease progression was confirmed in the treatment group, but not the gemfibrozil-treated A213 association with regression, suggesting a pharmacogenetic difference. Conclusions—Disease progression is associated with variation in AAT, and low AAT levels promote atherogenesis. (Arterioscler Thromb Vasc Biol. 2003;23:644-649.)