title: A single nucleotide polymorphism in the p27(Kip1) gene is associated with primary patency of lower extremity vein bypass grafts.
abstract: OBJECTIVE
  Factors responsible for the variability in outcomes after lower extremity vein bypass grafting (LEVBG) are poorly understood. Recent evidence has suggested that a single nucleotide polymorphism (SNP) in the promoter region of the p27(Kip1) gene, a cell-cycle regulator, is associated with coronary in-stent restenosis. We hypothesized an association with vein graft patency.
  
  
  METHODS
  This was a retrospective genetic association study nested within a prospective cohort of 204 patients from three referral centers undergoing LEVBG for claudication or critical ischemia. The main outcome measure was primary vein graft patency.
  
  
  RESULTS
  All patients were followed up for a minimum of 1 year with duplex graft surveillance (median follow-up, 893 days; interquartile range, 539-1315). Genomic DNA was isolated and SNP analysis for the p27(Kip1)-838C>A variants was performed. Allele frequencies were correlated with graft outcome using survival analysis and Cox proportional hazards modeling. The p27(Kip1)-838C>A allele frequencies observed were CA, 53%; CC, 30%; and AA, 17%, satisfying Hardy-Weinberg equilibrium. Race (P = .025) and history of coronary artery disease (P = .027) were different across the genotypes; all other baseline variables were similar. Primary graft patency was greater among patients with the -838AA genotype (75% AA vs 55% CA/CC at 3 years; P = .029). In a Cox proportional hazards model including age, sex, race, diabetes, critical limb ischemia, redo (vs primary) bypass, vein type, and baseline C-reactive protein level, the p27(Kip1)-838AA genotype was significantly associated with higher graft patency (hazard ratio for failure, 0.4; 95% confidence interval, 0.17-0.93). Genotype was also associated with early (0-1 month) changes in graft lumen diameter by ultrasound imaging.
  
  
  CONCLUSIONS
  These data suggest that the p27(Kip1)-838C>A SNP is associated with LEVBG patency and, together with previous reports, underscore a central role for p27(Kip1) in the generic response to vascular injury.
authors: Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, Calif 94143, USA. michael.conte@ucsfmedctr.org
authors: Michael S
authors: MS
authors: Conte
authors: Christopher D
authors: CD
authors: Owens
authors: Michael
authors: M
authors: Belkin
authors: Mark A
authors: MA
authors: Creager
authors: Karen L
authors: KL
authors: Edwards
authors: Warren J
authors: WJ
authors: Gasper
authors: Richard D
authors: RD
authors: Kenagy
authors: Renee C
authors: RC
authors: LeBoeuf
authors: Michael
authors: M
authors: Sobel
authors: Alexander
authors: A
authors: Clowes
mesh_terms: D000368:Aged; D016638:Critical Illness; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006083:Graft Occlusion, Vascular / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007383:Intermittent Claudication / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D007511:Ischemia / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D058729:Peripheral Arterial Disease / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D018616:Ultrasonography, Doppler, Duplex; D014481:United States; D058017:Vascular Grafting / Q000009:adverse effects*; D014654:Vascular Patency / Q000235:genetics*; D014680:Veins / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000637:transplantation*
chemical_list: C436291:CDKN1B protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27