Single nucleotide polymorphism associated with primary patency of lower extremity vein bypass grafts

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New data suggest that genetic predisposition may have an influence on the outcomes of lower extremity revascularisation, with the recent finding that a single nucleotide polymorphism (SNP) in the p27kip1 gene is significantly associated with vein bypass graft patency. Michael S Conte, Division of Vascular and Endovascular Surgery, University of California, San Francisco, USA, presented the results of a study at the Society for Vascular Surgery Annual Meeting, Chicago USA. The study was led by Conte and Alexander W Clowes of the University of Washington, Seattle.

“Factors responsible for the variability in the incidence of stenosis after vein bypass grafting are poorly understood. Recent evidence has suggested that a SNP in the promoter region of the p27kip1 gene, a cell cycle regulator, is associated with coronary in-stent restenosis,” Conte said. SNPs are common variants in the genome that differ by just a single nucleotide in a specific locus.

 

The investigators sought to test this association in patients undergoing lower extremity vein bypass grafts. The genetic association study was performed within a prospective cohort of lower extremity vein bypass patients (n=204; mean age 68 years; 72% male; 87% Caucasian) from three enrolling centres in the United States. All patients were followed for a minimum of one year with duplex graft surveillance (median follow-up 893 days). Genomic DNA was isolated from whole blood collected prior to surgery, and SNP analysis for the specific p27kip1 -838 C>A variants performed. Allele frequencies were determined and correlated with graft outcome using survival analysis and Cox proportional hazards modeling.

 

The p27kip1 -838 allele frequencies observed in the cohort were: AC 53%, CC 30%, and AA 17%. There were no differences in demographics or comorbidities among the genotype groups. Overall, primary graft patency was 68% at one year and 58% at three years. On univariate analysis, patients with the -838AA genotype had improved primary graft patency (75% AA vs. 55% AC/CC at three years, p=0.031; Figure). In a Cox proportional hazards model, which included age, gender, diabetes, critical limb ischaemia, redo (vs. primary) bypass, vein type, and elevated baseline C-reactive protein level, the p27kip1 -838AA genotype was significantly associated with improved primary graft patency with a hazard ratio of 0.4 (95% CI, 0.17–0.93).

 

In conclusion, Conte said, these data suggest that an SNP in the p27kip1 gene is significantly associated with vein bypass graft patency. “This genetic marker is also associated with outcomes of coronary stenting, suggesting a broadly important mechanism in vascular injury and healing. In our study, single nucleotide polymorphism frequencies and effect sizes observed were notably similar across three distinct geographic cohorts and two different vascular beds. These data represent the first demonstration of a genetic marker for lower extremity vein bypass graft patency, and may also suggest a target for specific therapy. Our next steps are to validate the findings in a larger prospective study, and to also look for similar associations in patients undergoing dialysis access procedures and endovascular interventions,” he said.


The study was supported by the National Heart, Lung and Blood Institute and by VascularCures, a non-profit medical research foundation of which Conte serves as chief medical officer. VascularCures is currently launching a major consortium initiative to characterise genetic and proteomic determinants of peripheral revascularisation outcomes.

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