Progression of atherosclerosis is associated with variation in the alpha1-antitrypsin gene.
OBJECTIVE
Alpha1-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.


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.
Talmud
Philippa J
PJ
Centre for Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, 5 University St, London WC1E 6JF, UK. p.talmud@ucl.ac.uk
Martin
Steve
S
Steiner
George
G
Flavell
David M
DM
Whitehouse
David B
DB
Nagl
Sylvia
S
Jackson
Richard
R
Taskinen
Marja-Riitta
MR
Frick
M Heikki
MH
Nieminen
Markku S
MS
Kesäniemi
Y Antero
YA
Pasternack
Amos
A
Humphries
Steve E
SE
Syvänne
Mikko
M
D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D015331:Cohort Studies; D003131:Combined Modality Therapy; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003925:Diabetic Angiopathies / Q000150:complications; D018450:Disease Progression; D005260:Female; D011345:Fenofibrate / Q000737:chemistry / Q000627:therapeutic use; D015248:Gemfibrozil / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011485:Protein Binding; D011487:Protein Conformation; D055502:Secondary Prevention; D013329:Structure-Activity Relationship; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications* / Q000235:genetics
D020413:3' Untranslated Regions; D000960:Hypolipidemic Agents; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase; D015248:Gemfibrozil; D011345:Fenofibrate