title: Progression of atherosclerosis is associated with variation in the alpha1-antitrypsin gene.
abstract: 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.
authors.affiliation: 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
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Steve
authors.initials: S
authors.lastname: Martin
authors.forename: George
authors.initials: G
authors.lastname: Steiner
authors.forename: David M
authors.initials: DM
authors.lastname: Flavell
authors.forename: David B
authors.initials: DB
authors.lastname: Whitehouse
authors.forename: Sylvia
authors.initials: S
authors.lastname: Nagl
authors.forename: Richard
authors.initials: R
authors.lastname: Jackson
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: M Heikki
authors.initials: MH
authors.lastname: Frick
authors.forename: Markku S
authors.initials: MS
authors.lastname: Nieminen
authors.forename: Y Antero
authors.initials: YA
authors.lastname: Kesäniemi
authors.forename: Amos
authors.initials: A
authors.lastname: Pasternack
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Mikko
authors.initials: M
authors.lastname: Syvänne
mesh_terms: 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
chemical_list: D020413:3' Untranslated Regions; D000960:Hypolipidemic Agents; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase; D015248:Gemfibrozil; D011345:Fenofibrate