CLINICAL RESEARCH STUDIES
From the Society for Vascular Surgery
A single nucleotide polymorphism in the p27Kip1
gene is associated with primary patency of lower
extremity vein bypass grafts
Michael S. Conte, MD,aChristopher D. Owens, MD,aMichael Belkin, MD,bMark A. Creager, MD,c
Karen L. Edwards, PhD,dWarren J. Gasper, MD,aRichard D. Kenagy, PhD,eRenee C. LeBoeuf, PhD,f
Michael Sobel, MD,c,gand Alexander Clowes, MD,eSan Francisco, Calif; Boston, Mass; and Seattle, Wash
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 p27Kip1gene, 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
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 p27Kip1-838C>A variants was
performed. Allele frequencies were correlated with graft outcome using survival analysis and Cox proportional hazards
modeling. The p27Kip1-838C>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 p27Kip1-838AA
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 p27Kip1-838C>A SNP is associated with LEVBG patency and, together
with previous reports, underscore a central role for p27Kip1in the generic response to vascular injury. (J Vasc Surg
First described more than 60 years ago,1autogenous
vein bypass grafting remains a key therapeutic option for
patients with extensive peripheral artery disease as well as
coronary artery disease. In the United States Medicare pop-
ulation, more than 100,000 lower extremity and 200,000
coronary bypass graft procedures are performed each year
for relief of ischemia.2,3Although vein grafts in the lower
extremity are durable in many cases, the development of
de novo stenosis within the graft occurs in 30% to 50% of
patients within the first several years, often necessitating
repeat intervention.4-8Despite attention to vein harvesting
trauma, improved surgical techniques, modification of con-
ventional atherosclerosis risk factors (eg, smoking cessation,
lipid-lowering drugs), and antithrombotic therapies, the in-
cidence of vein graft disease has not changed perceptibly
for 3 decades. Furthermore, there is limited understanding,
From the Division of Vascular and Endovascular Surgery, University of
California, San Francisco, San Franciscoa; the Divisions of Vascular
and Endovascular Surgery,band Cardiovascular Medicine,cBrigham
and Women’s Hospital, Boston; the Department of Epidemiology,
Institute for Public Health Genetics,dthe Department of Surgery,e
and the Department of Medicine,fand the Division of Vascular Surgery,
VA Puget Sound Health Care System,gUniversity of Washington,
Supported by funding from the National Heart, Lung and Blood Institute
(HL75771) to M.S.C., C.D.O., and M.A.C.; HL30946 to A.W.C. and
R.D.K.; HL098227 to R.C.L.; Department of Veterans Affairs Office
of Research Development, Clinical R&D to M.S.; and Vascular Cures
Research Foundation to M.S.C. and A.W.C.
Author conflict of interest: none.
Presented at the 2011 Vascular Annual Meeting of the Society for Vascular
Surgery, Chicago, Ill, June 16-18, 2011.
Additional material for this article may be found online at www.jvascsurg.org.
Reprint requests: Michael S. Conte, MD, Division of Vascular and
Endovascular Surgery, Heart and Vascular Center, University of
California, San Francisco, 400 Parnassus Ave, San Francisco, CA 94143
The editors and reviewers of this article have no relevant financial relationships
to disclose per the JVS policy that requires reviewers to decline review of any
manuscript for which they may have a conflict of interest.
Copyright ? 2013 by the Society for Vascular Surgery. Published by Elsev-
ier Inc. All rights reserved.
beyond technical factors, of the variable nature of vein
graft remodeling and clinical outcomes among individual
The prototypic response of blood vessels to mechanical
trauma, namely, the development of neointimal thickening,
may become clinically manifest as lumenal renarrowing after
angioplasty, stent placement, and bypass grafting. The acute
injury triggers a proliferative responsive in resident vascular
smooth muscle cells (VSMCs) and adventitial cells via cell-
cycle activation. Normally quiescent in the uninjured vessel,
VSMCs rapidly respond to local cytokine and growth factor
signals and are released from growth inhibition by coordi-
nated activity of cell cycle proteins.10
dependent kinase (CDK) inhibitor p27Kip1is a critical
by inhibiting CDK-cyclin interactions, specifically that
between cyclin E-CDK2 and cyclin D-CDK4.11Numerous
lines of evidence suggest that p27Kip1plays an important
role in the response to vascular injury and in atheroscle-
Recent studies have demonstrated the potential role of
genetic variability as a determinant of clinical outcomes in
patients with cardiovascular disease and after clinical inter-
ventions. Of interest, a single nucleotide polymorphism
(SNP) in the p27Kip1gene (-838C>A; rs36228499) was
recently identified as a potential risk factor for myocardial
infarction.15In a retrospective association study in two
Dutch cohorts of patients who had undergone percuta-
neous placement of bare-metal stents (BMS) in coronary
arteries, this single nucleotide polymorphism (SNP) was
identified as a strong predictor of in-stent restenosis.16
We hypothesized that genetic factors related to neointimal
disease in venous bypass grafts would be similar to those in
injured arteries and that variability in the p27Kip1gene
would be associated with vein graft disease. Our findings
support a potentially central role for p27Kip1as a global
determinant of cardiovascular intervention outcomes.
Study design and cohorts. This was a retrospective
study designed to test the specific hypothesis that the
p27Kip1-838C>A SNP (rs36228499) is associated with
primary patency of lower extremity vein bypass grafts
The primary cohort of 204 patients was derived from
a prospective study examining the relationship between
systemic inflammation and clinical outcomes after LEVBG
at three Boston hospitals (Brigham and Women’s Hospital,
Beth Israel Deaconess Medical Center, Boston VA Medical
Center). This study was sponsored by the National Heart,
Lung and Blood Institute (HL 75771). The inclusion and
exclusion criteria of this cohort have been described else-
where.17,18Briefly, patients were eligible for enrollment if
they were undergoing primary or redo lower extremity
bypass surgery with autogenous vein for lifestyle-limiting
claudication or critical limb ischemia. Importantly, patients
were excluded if they had a recent pre-existing condition
likelyto influence systemicinflammation, including
myocardial infarction, stroke, major illness, or major opera-
tion #30 days of the bypass surgery, evidence of foot infec-
tion, or current use of immunosuppressant medications.
Patients were also excluded if any portion of the bypass
was constructed with nonautogenous material.
All patients provided written informed consent, and the
study protocol was approved by the respective Institutional
Review Boards (IRBs) at the participating sites. Patients
were enrolled between 2004 and 2007 and were followed
up for a minimum of 1 year (median follow-up, 32 months).
A preoperative blood sample was drawn on all study partic-
ipants, and aliquots of anticoagulated whole blood were
frozen at –80?C. Of the 225 individuals enrolled in this
study, DNA samples were available for genotyping from
204, which are the subject of the analysis.
A second cohort of 51 patients examined in this study
was derived from two Seattle hospitals (University of Wash-
ington Medical Center and the VA Puget Sound Health
Care System). These individuals were enrolled in a series
of prospective, observational pilot studies examining the
associations between graft stenosis, platelet/monocyte
activity, and growth patterns of cells obtained from vein
grafts (Supplementary Table I).19,20The studies were
approved by the IRBs at both institutions, and all patients
gave informed consent. Patients were excluded if they were
unable to give informed consent or to return for follow-up
examinations. Participants in the Seattle cohort were
recruited between 2004 and 2009. Patients were followed
up for a minimum of 12 months. Anticoagulated whole
blood was obtained at baseline and frozen at –80?C.
Clinical assessments and end point definitions. All
patients in the Boston cohort were followed up by their
vascular surgeons for clinical and graft-related events at 1,
3, 6, 9, and 12 months, and every 6 months thereafter until
termination from the study. Study personnel recorded
clinical or graft-related events during the postoperative
visits, including rehospitalizations, major adverse cardio-
vascular events, amputations, graft revisions, or graft
occlusions. Under the study protocol, patients underwent
duplex ultrasound surveillance of their bypass grafts at each
visit at 1, 3, 6, 9, and 12 months, and thereafter at 6-month
intervals. For the Seattle cohort, the follow-up assessment
schedule included clinical and duplex ultrasound graft
examinations at 6 weeks and at 3, 6, and 12 months after
surgery. Primary and secondary graft patency were defined
in accordance with accepted guidelines for reporting of
lower extremity revascularization.21
Genomic DNA and SNP analysis. Genomic DNA
was isolated from whole blood using a purification kit and
the manufacturer’s suggested protocol (Wizard; Promega
Corp, Madison, Wisc). The p27Kip1-838C>A SNP was
genotyped by polymerase chain reaction using the follow-
ing primers: forward: TCCAGGTCCCGGCTTCCCGGt,
reverse: CCTGCTCTGGCTGGCCTCGGAG.A mismatch
creating a Taq1 site when -838C is present is shown in lower
case. Reactions were performed using a programmable ther-
mocycler (MJ Research, St. Bruno, Quebec, Canada), and
the reaction product was digested with Taq1 (10 hours at
JOURNAL OF VASCULAR SURGERY
1180 Conte et al
65?C) and resolved on a 3.5% agarose gel with ethidium
Ultrasound imaging substudy. We prospectively
enrolled patients from one of the study sites (Brigham and
Women’s Hospital in Boston) in an IRB-approved imaging
substudy designed to examine remodeling patterns in vein
bypass conduits using high-resolution ultrasound imaging.
The methods for this substudy have been reported previ-
ously.18In brief, after informed consent, participants
underwent serial ultrasound assessment of a defined, regis-
tered 5-cm region of their bypass graft using B-mode,
M-mode, and Doppler modalities. The designation of the
region of interest of the conduit (index segment) was made
in the operating room and was specifically selected as
a straight, valveless vein segment $5 cm away from the
proximal anastomosis and in a superficial location. Surgical
clips were placed as a reference, and the distance from the
proximal anastomosis was recorded for subsequent identifi-
room after completion of the bypassgraft andbeforewound
closure. Five high-resolution M-mode cross-sectional
images of the vein were recorded at each 1-cm interval
along the index segment using an ATL HDI 3000 ultra-
sound machine (Advanced Technology Laboratories,
Bothell, Wash) with a 10-MHz transducer and cardiac
gating. Lumen diameter was calculated as the mean of these
25 measurements. At postoperative visits, in addition to
standard Duplex graft surveillance, these patients had
detailed imaging acquisition of the index segment of the
conduit using the same protocol.
Statistical methods. Hardy-Weinbergequilibriumwas
first evaluated among the full Boston cohort and then in the
subset who self-reported as white. There were no significant
deviations from Hardy-Weinberg equilibrium (P > .20).
The primary analyses were performed using the larger
Boston cohort, with the Seattle cohort analyzed separately
as a confirmatory population. Graft patency rates were
estimated by life-table analysis. Univariate associations
between genotype and graft outcomes were performed by
log-rank test. A Cox proportional hazards model was used
incorporating demographic (age, race, sex) variables and
other variables relevant to LEVBG outcomes, including
diabetes, critical limb ischemia as the indication, redo
in addition to the p27 genotype. A value of P < .05 was
considered statistically significant for all tests.
Characterization of the study population by p27
genotype. Characteristics of subjects in the Boston cohort
by p27Kip1-838C>A genotype are summarized in Table I
(see Supplementary Table II, online only, for the Seattle
cohort). Mean age was 70 years, 82% were white, and 45%
were women. Race (P ¼ .025) and history of coronary
artery disease (P ¼ .027) were different across the geno-
types; all other baseline variables including use of anti-
platelet and statin medications were similar between the
groups. There were no failures of genotyping for this SNP.
The p27Kip1-838C>A allele frequencies observed were
CA, 53%; CC, 30%; and AA, 17% in the Boston cohort and
CA, 65%, CC 23%, and AA 12% in the Seattle cohort. Age,
race, and sex distributions for the Seattle cohort were
similar to that of the Boston cohort.
Clinical outcomes. For the Boston cohort, 78 patients
lost primary patency during follow-up. By life-table analysis,
the overall primary patency rate was 69% 6 3% at 1 year and
60% 6 4% at 3 years. Secondary patency was 85% 6 3% and
82% 6 3% at 1 and 3 years respectively.
Early (30-day) event rates were not different by
genotype (Table II). Primary graft patency tended to be
associated with p27Kip1-838 genotype, with the patients
having the AA genotype demonstrating improved patency
(P ¼ .066 by log-rank test; Table II; Fig 1). Because the
observed pattern was consistent with a recessive model,
we combined the CA and CC groups for subsequent anal-
ysis. In this analysis, AA genotype was significantly associ-
ated with primary graft patency (P ¼ .029 by log-rank
test; Fig 2).
In the Seattle cohort, a similar trend was observed in
primary patency by p27Kip1-838C>A genotype (83% AA
vs 60% CA/CC at 1 year; P ¼ .27 by c2; Supplementary
Table III, online only).
Multivariable model for primary graft patency.
A Cox proportional hazards model using the Boston cohort
Table I. Characteristics of Boston lower extremity vein
bypass (LEVB) graft cohort by the p27Kip1-838 genotype
hsCRP >5 mg/L
67.3 6 12.1 66.8 6 67.5 67.8 6 9.95 .891
26 (74.3) 81 (75.0)
108 (52.9)61 (29.9)
40 (65.6) .402
27.1 6 5.03 29.1 6 7.4
28.7 6 7.36 .325
17 (48.6)47(43.5)36 (59.0).153
BMI, Body mass index; CAD, coronary artery disease; CLI, critical limb
ischemia; hsCRP, high-sensitivity C-reactive protein; SSGSV, single-segment
great saphenous vein.
aContinuous data re shown as mean 6 standard deviation and categoric data
as number (%).
JOURNAL OF VASCULAR SURGERY
Volume 57, Number 5
Conte et al 1181
data revealed that the p27Kip1-838C>A genotype was
significantly associated with primary graft patency (hazard
ratio for AA, 0.41; 95% confidence interval, 0.18-0.97;
P ¼ .039), adjusting for age, race, diabetes, redo bypass,
indication (critical ischemia vs claudication), and baseline
high-sensitivity C-reactive protein (Table III). Analyses
restricted to the individuals who self-reported as white race
had very similar point estimates (hazard ratio for AA, 0.39;
95% confidence interval, 0.16-0.99; P ¼ .048) including
adjustment for the same set of covariates.
Vein remodeling. We analyzed data from the imaging
substudy to look for associations between patterns of
vein remodeling after arterialization and the p27Kip1-838
genotype. There were 55 patients who participated in the
ultrasound substudy, had imaging data available from
the intraoperative and 1-month scans, and had been geno-
typed for the p27 SNP of interest. We found that individuals
with the homozygous CC genotype had significantly less
early dilation (0-1 month) of the venous conduit (P ¼ .045
by analysis of variance; Fig 3). This association was
unchanged when restricted to the 45 white patients. Owing
define significant associations between genotypes and later
remodeling changes or to conduct further multivariable
analysis across genotypes.
Comparison with other cohorts. Table IV summa-
rizes the genotype frequencies, prevalence of stenosis
(artery or graft), and point estimate effect size for the
Boston and Seattle vein graft cohorts compared with the
coronary BMS outcomes in the Dutch cohort reported by
van Tiel et al.16Reflective of a largely white population in
the current study populations, likely enriched for European
descent, the genotype frequencies seen are broadly similar
across the North American and Dutch cohorts. The
protective AA genotype was present in 12% to 21% of these
populations. The strikingly similar estimates of a protec-
tive association between the AA genotype and target
vessel stenosis across the peripheral bypass and coronary
BMS studies suggest a fundamental association between
p27Kip1-838C>A genotype and the vascular injury res-
ponse in disparate vessels and circulatory beds.
To our knowledge, this report identifies the first poten-
the promoter region (position -838) of the gene for the cell-
cycle inhibitor, p27Kip1. Patients homozygous for the minor
variant A allele, roughly one of six individuals in the study
population, experienced a 2.5-fold reduction in subsequent
graphic and clinical risk factors even in a modest-sized pop-
ulation, which suggests it is likely robust. Moreover, the
tive validation, they suggest a potentially important global
marker of genetic variability in the vascular injury response.
role in the regulation of vascular cell proliferation, with
and human vascular lesions.10,13,22After arterial injury,
increased p27Kip1expression coincides with decreased cel-
lular proliferation by 5-bromo-2-deoxyuridine staining.12
Genetic studies in mice demonstrate a prominent inhibitory
mal hyperplasia.23In a rabbit vein graft model, local treat-
ment with rapamycin resulted in elevated levels of p27Kip1
that correlated directly with reduced proliferation and less
early intimal thickening.24
Current understanding of the adaptive process of vein
disease in humans remains quite incomplete. After
Table II. Summary of clinical outcomes in Boston
cohort by p27Kip1-838 genotype
MACE, Major adverse cardiovascular event, including death, myocardial
infarction, stroke; SEM, standard error of the mean.
aAll rates >30 days are by life-table analysis, shown as % (SEM); 30-day
event rates are raw proportion.
bUnivariate P-values by log-rank or logistic regression analysis.
Fig 1. Life-table plot shows primary lower extremity vein bypass
graft patency by p27kip1-838 genotype for the 204 individuals in
the Boston cohort. Data are shown with the standard error of the
JOURNAL OF VASCULAR SURGERY
1182 Conte et al
implantation in the arterial circulation, veins must undergo
structural remodeling in response to acutely elevated shear
and tensile forces, leading to some requisite wall thickening.
An integrated biomechanical/biochemical approach is
needed to explain the observed variability in this response,
both along the course of a given conduit and among indi-
vidual patients.25Lumen caliber in the vein graft is deter-
mined by wall thickness and remodeling. We have
previously reported the time course and variability of vein
graft remodeling in the lower extremity, highlighting the
uals with the homozygous p27Kip1-838CC genotype had
notably inferior remodeling during the first postoperative
month. These data, although preliminary, suggest that
imaging is limited to lumen dimensions, we are not able to
consisting of several factors, including remodeling, wall
thickness, and thrombosis. We postulate that the apparent
discrepancy between a dominant vs a recessive influence of
these different components.
Interest in blocking cell cycle activation as a means of
reducing neointimal thickening in bypass grafts stems from
a large body of animal and in vitro studies. Of note, the
PRoject of Ex-Vivo vein graft ENgineering via Transfection
(PREVENT) clinical trials tested a molecular strategy of
eral), both of which were negative.27,28The reasons for
failure of the test agent in these studies remain unclear;
however, variability in clinical outcomes across a range of
patient-level factors, including race and sex, was observed
describing genetic association studies in vein bypass
outcomes,29-31and none involving peripheral grafting.
Importantly, our study was not a broad exploratory investi-
gation of genetic associations but rather a hypothesis-based
Fig 2. Life-table plot shows primary lower extremity vein bypass
graft patency by p27Kip-838 genotype, using a recessive model (AA
vs CA þ CC). Data are shown with the standard error of the mean.
Table III. Cox proportional hazards model for primary
VariableHR (95% CI)
Critical limb ischemia
Baseline hs-CRP >5 mg/L
CI, Confidence interval; HR, hazard ratio; hs-CRP, high-sensitivity
aThere is no corresponding footnote for “a” in Table III.
Fig 3. Percentage change (mean 6 standard deviation) is shown
in vein graft lumen diameter from baseline (intraoperative after
implantation) to 1 month, in a subset of 55 patients who took part
in a detailed ultrasound imaging substudy,18by p27Kip1-838
genotype (P ¼ .045 by analysis of variance).
Table IV. Relative effects size of the AA genotype in
three different cohorts
of stenosis, %
of effect size
HR, Hazard ratio, OR, odds ratio.
JOURNAL OF VASCULAR SURGERY
Volume 57, Number 5
Conte et al 1183
testing of a single suspected genetic marker based on the
recent coronary studies.
One of the salient findings from this study is the striking
the p27Kip1-838C>A SNP across our two geographic
centersandone inEurope,andtwodistinct typesofvascular
injury (stent in the coronary artery and vein bypass in
the leg). Although clearly requiring further larger-scale vali-
unique clinical and biologic significance. The initial report
from Gonzalez et al16linking the p27Kip1-838C>A SNP
is the differential role of VSMC proliferation in maintaining
fibrous cap integrity of native atherosclerosis lesions vs
promoting restenosis, as a logical explanation that requires
This investigation has a number of important limita-
tions, among which the modest size and limited diversity
of the study population is paramount. Nevertheless, this
limitation is counterbalanced by the considerable power
of long-term imaging surveillance of the bypass grafts in
these individuals, allowing for accurate assessment of the
timing and progression of vein graft lesions that is not
generally obtainable in coronary studies.
Second, we do not have evidence to directly link the
p27Kip1-838C>A SNP to expression of p27Kip1within
tissue from the patients. Therefore we cannot discriminate
between association and causation in our findings. Of note,
van Tiel et al16examined the potential functional signifi-
cance of the p27Kip1-838C>A SNP using a recombinant
promoter-luciferase construct in human embryonic kidney
293 cells, demonstrating a large increase in promoter
activity with the -838A construct compared with the
-838C construct. In preliminary studies using these iden-
tical constructs (courtesy Carlie J. M. deVries), we have
kidney 293 cells and in primary cultured adventitial fibro-
blasts from human saphenous vein (Supplementary Fig,
online only). However, more direct evidence linking tissue
expression to p27Kip1genotype is needed to support the
hypothesis for causation.
peripheral arterial disease remain high, and the prediction
and prevention of such failures is a significant unmet clinical
need. Our studies support the need for broader efforts to
of restenosis. These findings highlight that such efforts
should consider common phenotypic patterns between
different types of interventions and vascular beds as well as
other related forms of mechanical and surgical trauma. As
one example, the p27Kip1-838C>A SNP is a commonly
encountered genetic variant that may help to explain some
of the unpredictable failure risk associated with therapeutic
We acknowledge Carlie J. M. deVries (University of
Amsterdam) for providing primer sequences, variant p27
promoter constructs, and for scientific advice in the geno-
typing experiments. Diana Kim assisted with management
of the clinical database and blood samples for this project.
Genomic DNA extraction was performed by the University
of California, San Francisco, DNA Bank. Mark Caldwell
provided technical assistance with sample genotyping. We
also acknowledge participating surgeons from the Boston
and Seattle hospitals who enrolled patients in the respective
cohort studies used for this analysis, particularly Drs. Allen
D. Hamdan (Beth Israel Deaconess Medical Center,
Boston), Frank B. Pomposelli Jr (Beth Israel Deaconess
Medical Center, Boston), and Joseph D. Raffetto (Boston
VA Medical Center, Boston). Lihua Chen, PhD, assisted
with performance of the p27 promoter assays.
Conception and design: MC, AC
Analysis and interpretation: MC, CO, MB, MC, KE, WG,
RK, RL, MS, AC
Data collection: MC, CO, RK
Writing the article: MC, CO, KE, WG, RK, RL, AC
Critical revision of the article: MC, CO, MB, MC, KE,
WG, RK, RL, MS, AC
Final approval of the article: MC, CO, MB, MC, KE, WG,
RK, RL, MS, AC
Statistical analysis: MC, CO, KE, WG, RK
Obtained funding: MC
Overall responsibility: MC
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HarringtonRA, Peterson ED,
Submitted Jul 20, 2012; accepted Nov 3, 2012.
Additional material for this article may be found online
JOURNAL OF VASCULAR SURGERY
Volume 57, Number 5
Conte et al 1185
Supplementary Table I (online only). Patient inclusion and exclusion criteria for Seattle cohort
Type of surgical
Elective infrainguinal arterial bypass with
autogenous vein for claudication or critical
limb ischemia due to chronic atherosclerotic
occlusive disease. Simultaneous endovascular
inflow procedures permitted.
Autogenous vein graft >15 cm, including
high-risk vein graftsa(single or spliced non-GSV
segments, vein diameter <3 mm, surgical revisions
or corrections performed at index operation).
Stable malignancy (eg, prostate cancer)a
Any type of antithrombotic therapya
Renal impairment (if BUN <60 mg/dL)a
Previously failed leg bypassa
Agea: >18 years; racea: all races
Operations for nonatherosclerotic, or aneurysmal
disease. Simultaneous femoralefemoral, or
aortobifemoral bypass. Post-op graft thrombosis
for technical reasons, within the first 30 days.
Composite grafts that include prosthetic conduits.
Thrombectomy and/or revision of an existing graft.
Actively progressive malignancy
Chemotherapy for malignancy (#3 months)
Renal failure (dialysis)
Systemic inflammatory disease (eg, lupus)
A diagnosed hypercoagulable state
Agea: <18 years
Already enrolled in an investigational drug study.
Previously enrolled in this study.
Can’t follow-up, expected survival <6 months.
BUN, Blood urea nitrogen; GSV, great saphenous vein.
aThese conditions are identified as prospective covariables.
Supplementary Table II (online only). Characteristics
of Seattle cohort by p27Kip1-838 genotype
69.3 6 12.6
65.4 6 7.9
63.8 6 6.8
CAD, Coronary artery disease; CLI, critical limb ischemia; CVD, cerebro-
aContinuous data are shown as mean 6 standard deviation and categoric
data as number (%).
Supplementary Table III (online only). Summary of
clinical outcomes in Seattle cohort by p27Kip1-838
Loss of primary patency 1 (17) 15 (44)3 (25) 19 (37)
JOURNAL OF VASCULAR SURGERY
1185.e1 Conte et al
-838C -838A Download full-text
Supplementary Fig (online only). Effect of the p27kip1-838C>A
polymorphism on p27Kip1promoter activity in human venous
fibroblasts. Primary cultured adventitial fibroblasts from human
saphenous vein (Kenagy et al J Vasc Surgery 2009; 49:1282-8)
were transfected by electroporation with the indicated p27Kip1
promoter-luciferase constructs used by van Tiel et al (Circulation
2009; 120:669-676) containing the -838A or -838C variant. One
day after transfection, cells were changed to serum-free medium for
24 hours and firefly luciferase activity measured. Luciferase activity
was normalized to Renilla luciferase and expressed as fold of the
empty pGL3 shuttle vector. Data shown are mean of four inde-
pendent experiments (P < .006 by paired t-test).
JOURNAL OF VASCULAR SURGERY
Volume 57, Number 5
Conte et al 1185.e2