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

Abstract

Objective— α 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.