title: Neutrophil elastase gene variation and coronary heart disease.
abstract: OBJECTIVE
  Identification and functional characterization of variants in the neutrophil elastase (ELA2) gene in cardiovascular disease.
  
  
  METHODS
  From participants of the ECTIM (Etude Cas-Témoins sur l'infarctus du Myocarde) Study with myocardial infarction (MI) 2082 chromosomes were genetically scanned; 990 patients with MI and 904 controls were genotyped for the common polymorphisms G-761A and S173S (C4890A). Expression vectors for Ela2 variants were transiently transfected, followed by Northern and Western blot analyses. Promoter variants were analyzed by transfection/reporter gene assays.
  
  
  RESULTS
  We identified 11 genetic variants, two in the 5'-flanking (G-761A, -852/del53 bp), six in exons (R49H, N81N, G93V, S173S, D222Y, P228L) and three in introns (C+29/in3T, C+149/in3T, C+137/in4T). In Belfast, 4890A allele carriers had a risk for MI with an odds ratio (OR) of 1.44 (95% CI 1.12-1.86; P=0.005), the OR for MI associated with the -761G/-4890A haplotype with reference to -761G/-4890C amounting to 2.38 (95% CI 1.23-4.57; P=0.01). Transcript or protein expression of both allelic constructs (4890A and 4890C) did not, however, differ. Conversely, transcriptional activity was significantly elevated (<35%) by -852/del53 bp in THP-1 monocytes compared with the nondeleted promoter (P=0.001); the deletion was observed in one patient with premature MI at the age of 28 years, whose mother had had an MI at the age of 48 years.
  
  
  CONCLUSIONS
  The association of C4890A with MI in Belfast exclusively, and the presumed absence of its functionality, provides little support for a substantial implication of common ELA2 gene variants in overall MI risk. Whether -852/53del plays a role in cardiovascular pathophysiology or not should be evaluated further.
authors.affiliation: Department of Molecular Genetics of Cardiovascular Disease, Leibniz-Institute for Arteriosclerosis Research, University of Muenster, Muenster, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schönfelder
authors.forename: Ralph
authors.initials: R
authors.lastname: Telgmann
authors.forename: Viviane
authors.initials: V
authors.lastname: Nicaud
authors.forename: Eva
authors.initials: E
authors.lastname: Brand
authors.forename: Corinna
authors.initials: C
authors.lastname: Dördelmann
authors.forename: Christina
authors.initials: C
authors.lastname: Rüssmann
authors.forename: Katrin
authors.initials: K
authors.lastname: Beining
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmidt-Petersen
authors.forename: Alun
authors.initials: A
authors.lastname: Evans
authors.forename: Frank
authors.initials: F
authors.lastname: Kee
authors.forename: Caroline
authors.initials: C
authors.lastname: Morrison
authors.forename: Dominique
authors.initials: D
authors.lastname: Arveiler
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.forename: Martin
authors.initials: M
authors.lastname: Paul
authors.forename: Stefan-Martin
authors.initials: SM
authors.lastname: Brand-Herrmann
mesh_terms: D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D020029:Base Pairing; D016022:Case-Control Studies; D002460:Cell Line; D003327:Coronary Disease / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D019272:Leukocyte Elastase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D012333:RNA, Messenger; D019272:Leukocyte Elastase