title: Haplotype of growth hormone and angiotensin I-converting enzyme genes, serum angiotensin I-converting enzyme and ventricular growth: pathway inference in pharmacogenetics.
abstract: OBJECTIVE
  An insertion/deletion (I/D) polymorphism in the angiotensin I-converting enzyme (ACE) gene is associated with variations in circulating and tissue angiotensin I-converting enzyme activity, and differences in exercise-induced left ventricular hypertrophic response. A genetic marker (CSH1.01) in the syntenic GH-CSH gene cluster correlates with metabolic syndrome in adult life in males. Approximately 24% linkage disequilibrium between CSH1.01T and D alleles of ACE I/D has also been reported. The objective was to examine the hypothesis that effects ascribed to ACE genotype may reflect causality in the GH-CSH cluster.
  
  
  METHODS
  The ACE I/D polymorphism and GH-CSH BglII-B single nucleotide polymorphism (in strong linkage disequilibrium with CSH1.01) were determined in 847 British Army recruits. Serum angiotensin I-converting enzyme activity and left ventricular mass were measured before and after a 12-week physical training program. Genotype and haplotype analyses of both markers were performed in relation to these phenotypes.
  
  
  RESULTS
  The ACE I/D polymorphism was in linkage disequilibrium with BglII-B (D'=0.3). Strong association was seen between ACE I/D genotypes and serum angiotensin I-converting enzyme activity (P<0.0001), but not left ventricular mass change. BglII-B genotypes also associated significantly with serum angiotensin I-converting enzyme level (P<0.0001). Haplotype analysis, however, showed that most of this association resulted from linkage disequilibrium between BglII-B and ACE I/D. BglII-B did not associate with left ventricular mass change.
  
  
  CONCLUSIONS
  GH-CSH BglII-B genotype associates significantly with angiotensin I-converting enzyme levels, but only through linkage disequilibrium with ACE I/D. Every phenotype with which ACE I/D has been associated merits investigation of potential causal effects originating in the GH-CSH cluster (and vice versa), otherwise the chain of causality could be misinterpreted.
authors.affiliation: National Genetics Reference Laboratory (Wessex), Salisbury District Hospital.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Huang
authors.forename: Xiao-He
authors.initials: XH
authors.lastname: Chen
authors.forename: John R
authors.initials: JR
authors.lastname: Payne
authors.forename: Dudley J
authors.initials: DJ
authors.lastname: Pennell
authors.forename: Peter
authors.initials: P
authors.lastname: Gohlke
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Smith
authors.forename: Ian N M
authors.initials: IN
authors.lastname: Day
authors.forename: Hugh E
authors.initials: HE
authors.lastname: Montgomery
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
mesh_terms: D000328:Adult; D005838:Genotype; D006239:Haplotypes; D019382:Human Growth Hormone / Q000235:genetics*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008889:Military Personnel; D007703:Peptidyl-Dipeptidase A / Q000097:blood* / Q000235:genetics*; D010597:Pharmacogenetics; D010809:Physical Fitness / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom
chemical_list: D019382:Human Growth Hormone; D007703:Peptidyl-Dipeptidase A