Relationships between serum MCP-1 and subclinical kidney disease: African American-Diabetes Heart Study
Relationships between serum MCP-1 and subclinical kidney disease: African American- Diabetes Heart Study
Mariana Murea 0 1
Thomas C Register 1
Jasmin Divers 1
Donald W Bowden 1
J Jeffrey Carr 1 3
Caresse R Hightower 1 3
Jianzhao Xu 1
S Carrie Smith 1
Keith A Hruska 1 2
Carl D Langefeld 1
Barry I Freedman 0 1
0 Department of Internal Medicine/Nephrology, Wake Forest School of Medicine, Medical Center Boulevard , Winston-Salem, NC 27157-1053 , USA
1 of Internal Medicine/Endocrinology/Centers for Diabetes Research and Human Genomics, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157 , USA
2 Division of Pediatric Nephrology, Washington University School of Medicine , St. Louis, MO 63110 , USA
3 Department of Radiology, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157 , USA
Background: Monocyte chemoattractant protein-1 (MCP-1) plays important roles in kidney disease susceptibility and atherogenesis in experimental models. Relationships between serum MCP-1 concentration and early nephropathy and subclinical cardiovascular disease (CVD) were assessed in African Americans (AAs) with type 2 diabetes (T2D). Methods: Serum MCP-1 concentration, urine albumin:creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and atherosclerotic calcified plaque (CP) in the coronary and carotid arteries and infrarenal aorta were measured in 479 unrelated AAs with T2D. Generalized linear models were fitted to test for associations between MCP-1 and urine ACR, eGFR, and CP. Results: Participants were 57% female, with mean ± SD (median) age 55.6±9.5 (55.0) years, diabetes duration 10.3±8.2 (8.0) years, urine ACR 149.7±566.7 (14.0) mg/g, CKD-EPI eGFR 92.4±23.3 (92.0) ml/min/1.73m2, MCP-1 262.9±239.1 (224.4) pg/ml, coronary artery CP 280.1±633.8 (13.5), carotid artery CP 47.1±132.9 (0), and aorta CP 1616.0±2864.0 (319.0). Adjusting for age, sex, smoking, HbA1c, BMI, and LDL, serum MCP-1 was positively associated with albuminuria (parameter estimate 0.0021, P=0.04) and negatively associated with eGFR (parameter estimate −0.0003, P=0.001). MCP-1 remained associated with eGFR after adjustment for urine ACR. MCP-1 levels did not correlate with the extent of CP in any vascular bed, HbA1c or diabetes duration, but were positively associated with BMI. No interaction between BMI and MCP-1 was detected on nephropathy outcomes. Conclusions: Serum MCP-1 levels are associated with eGFR and albuminuria in AAs with T2D. MCP-1 was not associated with subclinical CVD in this population. Inflammation appears to play important roles in development and/or progression of kidney disease in AAs.
African Americans; Albuminuria; Atherosclerotic calcified plaque; Diabetes; GFR; MCP-1
Inflammation, influx of circulating inflammatory cells,
synthesis and secretion of chemokines and cytokines
play important roles in diabetic kidney disease and
atherosclerosis [1,2]. The relationship between serum
chemokine monocyte chemoattractant protein-1 (MCP-1,
or CCL2) levels with kidney disease and subclinical
cardiovascular disease (CVD) has not been evaluated in the
African American (AA) population. Macrophages
contribute to the pathophysiology of atherosclerosis,
albuminuria, diabetic nephropathy (DN), and kidney failure
[3,4]. Macrophage trafficking and influx to the blood
vessel wall is driven in part by chemokines, and MCP-1
inhibition delays formation of atherosclerotic plaque .
In experimental and human DN, macrophages are the
principal infiltrating leukocyte population and the degree
of macrophage influx and MCP-1 expression in the
glomerular and interstitial compartments correlate with
albuminuria and kidney function outcome [4,6-8].
Experimentally, MCP-1 suppression ameliorated
albuminuria and kidney interstitial disease .
Albuminuria and kidney disease are strongly linked
with CVD. Presence of a graded association has been
demonstrated between estimated glomerular filtration
rate (eGFR) and albuminuria, with cardiovascular events,
mortality, and presence and severity of coronary artery
calcification (CAC) in European-derived populations
[9-11]. Despite presence of more severe conventional
CVD risk factors, AAs have markedly lower amounts of
CAC, carotid artery CP, and aorta CP than EAs [12,13],
along with significantly reduced rates of myocardial
infarction when provided equal access to healthcare [14-16].
Relationships between conventional CVD risk factors and
subclinical CVD do not appear to differ by race,
suggesting that novel risk factors including cytokines and genetic
variation may contribute to population-specific risks for
CP and CVD .
As inflammation has emerged at the core
pathophysiology of both diabetic nephropathy and atherosclerosis,
we sought to investigate the relationships between serum
MCP-1 concentrations with albuminuria, kidney
function, and vascular calcification in a well-characterized
cohort of AAs with type 2 diabetes (T2D) in the African
American-Diabetes Heart Study (AA-DHS). Previous
reports indicated that inflammation is a protracted
process, occurring from the early stages of nephropathy
(eGFR >90ml/min/1.73m2 and microalbuminuria) in
patients with type 1 diabetes (T1D) [18,19]. Presence of
inflammation in patients with chronic kidney disease
(CKD) has been associated with carotid intimal-medial
thickness  and increased risk of cardiovascular death
. Similarly, vascular endothelial damage begins
before it becomes clinically apparent, at early stages of
kidney disease (GFR >90 ml/min/1.73m2) . Elucidation
of inflammatory markers with impact on early kidney
disease and vascular dysfunction may guide innovative
therapies to prevent or reverse nephropathy and/or
vascular damage. We hypothesized that serum MCP-1
concentration, a surrogate of systemic and vascular inflammation,
changes in T2D patients in relation to kidney
function and vascular integrity. As such, the relationships
between serum MCP-1 concentrations with early
diabetic nephropathy and vascular calcified plaque were
The AA-DHS is an observational study conducted on a
cohort of self-reported and unrelated AAs with T2D
lacking advanced nephropathy. Participants with advanced
nephropathy or end-stage renal disease were excluded.
Recruitment was conducted from internal medicine clinics
and community advertising, as previously published .
Briefly, participant examinations were conducted in the
Clinical Research Unit of Wake Forest Baptist Medical
Center and included interviews for medical history and
health behaviors, anthropometric measures, resting blood
pressure (BP), electrocardiography, fasting blood sampling
(total cholesterol, low density lipoprotein [LDL]
cholesterol, high density lipoprotein [HDL] cholesterol,
triglycerides, hemoglobin A1c [HbA1c], glucose and high
sensitivity C-reactive protein [hsCRP]), spot urine
collection for albumin:creatinine ratio (ACR), and
computed tomography (CT).
History of CVD was provided by participant report
and medical record review. Individuals with a history
of myocardial infarction or stroke were included;
however, CP scores in the coronary arteries were excluded
in participants who underwent prior coronary artery
bypass grafting and in the carotid arteries in
participants who underwent carotid endarterectomy. We
assessed eGFR using the simplified MDRD study and
CKD-EPI equations [24,25]. Serum creatinine
concentration was measured using a modified kinetic Jaffe method
and corrected for inter-laboratory differences and
calibrated to the Cleveland Clinic . Medications known
to influence atherosclerosis (lipid lowering medications)
and urine ACR (angiotensin-converting enzyme
inhibitors [ACEi] and angiotensin-receptor blockers [ARB])
were recorded. The study was approved by the
Institutional Review Board at the Wake Forest School of
Medicine and all participants provided written informed
CP in the coronary arteries (CAC), carotid arteries
(CarCP), and infrarenal aorta (AorCP) were determined
using multidetector computed tomography (MDCT4)
with cardiac gating and capable of 500-millisecond
temporal resolution using the segmented reconstruction
algorithm (LightSpeed Qxi; General Electric Medical
Systems, Waukesha, WI, USA). Techniques for the
coronary and carotid scans have been described in detail
. In brief, participants were placed in the supine
position on the CT couch over a quality control calibration
phantom (Image Analysis, Inc., Columbia, KY, USA) for
scans of the heart and abdomen. The abdomen scan
series was used to measure AorCP. Technical factors for
this series were: 120 kV, 250 mA, 0.8-second gantry
rotation helical mode (7.5 mm/s), 2.5-mm slice thickness,
and standard reconstruction kernel. The display field of
view was 35 cm, resulting in a pixel dimension of 0.68
by 0.68 mm. CT scans of the three vascular territories
were analyzed on a G.E. Advantage Windows
Workstation with the SmartScores software package (General
Electric Medical Systems) using a modified Agatston
scoring method, which adjusts for slice thickness and
uses the conventional threshold of 130 Hounsfield units.
Serum MCP-1 was measured using an enzyme-linked
immunosorbent assay (ELISA) (QuantikineW Human
CCL2/MCP-1 ELISA; R&D Systems, Minneapolis) in
freshly thawed serum samples which had been stored at
-80C since collection. Analyses were performed in
batches using ELISA kits from a single lot to minimize
variability due to manufacturing variation. Intra- and
inter-assay coefficients of variation for MCP-1 were
4.0%/3.4% at 62.5 pg/ml and 1.8%/2.1% at 500 pg/ml.
Generalized linear models (GLM) were fitted to test for
associations between serum MCP-1 concentration and
diabetes duration, HbA1C, body mass index (BMI), urine
ACR, eGFR, CAC, CarCP and AorCP . MCP-1
values greater than 486.7 pg/ml, corresponding to the
95th percentile in the distribution, were winsorized to
486.7 . The Box-Cox method was applied to identify
the appropriate transformation best approximating the
distributional assumptions of conditional normality and
homogeneity of variance of the residuals . This
method suggested taking the natural log of (CAC+1),
(CarCP+1) and (AorCP+1), (ACR+1), CRP, MDRD and
CKD eGFR, the inverse of HbA1c and the inverse square
root of BMI to minimize the influence of extremely large
covariate values on parameter estimates in the models.
No transformation was required for eGFR. GLM models
were fitted using the winsorized values of MCP-1 as the
dependent variable. After an unadjusted analysis,
adjustments for age, sex, smoking, HbA1c, BMI, and LDL
levels were incorporated. Urine ACR was analyzed both
as categorical variable and as a continuous variable. The
models used to test for association between BMI and
HbA1c with MCP-1 contained one less variable than the
fully adjusted models between MCP-1 and other
variables. Inter-active effects between BMI and MCP-1 on
kidney function measures were also performed.
Interaction effects were evaluated by testing for the direct
interaction effect by including the centered product of
BMI by MCP-1 and performing the association analysis
between MCP-1 and the kidney function measures
stratified by BMI where the sample was stratified into
two subgroups (non-obese: BMI <30.0 kg/m2 and obese:
BMI ≥ 30.0 kg/m2). Type III sum of squares were also
computed to evaluate the effect of eGFR adjusted for
ACR (and vice-versa) and all other covariates on the
vascular calcification and renal function measures.
The study included 479 unrelated AAs with T2D (57%
women), 50.7% with hypertension (HTN), with mean ±
SD (median) age 55.6 ± 9.5 (55.0) years, diabetes
duration 10.3 ± 8.2 (8.0) years, and BMI 35.5 ± 8.7 (34.0)
kg/m2 (Table 1). Participants were stratified by baseline
urine ACR into non-albuminuric (urine ACR <30 mg/g;
n=300) and albuminuric (urine ACR ≥30 mg/g; n=179).
Characteristics of the cohort included serum MCP-1
levels 262.9 ± 239.1 (224.4) pg/ml, hsCRP 1.1 ± 1.8 (0.5)
mg/dl, MDRD eGFR 95.2 ± 27.2 (93.3) ml/min/1.73m ,
CKD-EPI eGFR 92.4 ± 23.3 (92.0) ml/min/1.73m2, and
urine ACR 149.7 ± 566.7 (14.0) mg/g. There were no
between gender differences in serum MCP-1 levels (267.8 ±
242.0 (229.3) pg/ml in women, and 256.5 ± 235.4
(212.8) pg/ml in men, P=0.26). CAC was present in
62.7% of participants, 48.5% had detectable CarCP, and
77.9% detectable AorCP. CKD-EPI and MDRD
determined eGFRs were highly correlated (Spearman
Subjects with albuminuria had a longer diabetes
duration by mean ± SD 2.1 ± 0.2 years (P=0.0007), higher
prevalence of HTN (62% vs. 44%, P=0.0001), higher BP
values with mean ± SD difference of 8.9 ± 5.4 mmHg in
systolic BP (P<0.0001) and 2.9 ± 0.9 mmHg in diastolic
BP (P=0.008), and were more often prescribed ARB and
insulin (Table 1). Differences in biochemical parameters
were also noted, with the albuminuric group having
higher HbA1c, total cholesterol, triglycerides, and serum
creatinine; and lower fasting glucose and HDL (Table 2).
Modeled as a continuous variable, albuminuria was
negatively associated with eGFR (parameter estimates
and P-values of −0.0014 and 0.04 for CKD-EPI eGFR,
and −0.0015 and 0.06 for MDRD eGFR).
In the univariate analysis, serum MCP-1 levels had
negative association with Log (eGFR) and trended
towards positive association with Log (urine ACR+1).
Adjusted models including demographic characteristics
(age, sex, smoking, BMI,) and laboratory values (HbA1c,
LDL) maintained significant evidence of negative
association between MCP-1 and Log (eGFR) (parameter
estimate −0.0003, P=0.001) and detected significant positive
association with urine ACR after logarithmic
transformation (parameter estimate 0.0021, P=0.04) (Table 3).
Since urine ACR is associated with eGFR, we analyzed
the relationship between MCP-1 and eGFR based on
adjusting for Log (ACR+1), in a fully adjusted model.
Compared to ACR alone (parameter estimate −0.0135,
P=0.05), MCP-1 had the strongest association with
CKD-EPI eGFR (parameter estimate −0.0004, P=0.002)
We next assessed whether there is a correspondence
between MCP-1, ACR, eGFR, and vascular CP. No
association was detected between MCP-1 and CAC, CarCP,
or AorCP in either unadjusted or adjusted models
(Table 3). However, albuminuria was independently and
significantly associated with vascular CP in all three
vascular beds, while eGFR did not exhibit an association
Relationships between serum MCP-1 with diabetes
duration, BMI, and hsCRP were also assessed. No
correlations were observed between serum MCP-1 and
diabetes duration or hsCRP. Serum MCP-1 levels correlated
with BMI, and this remained significant in the adjusted
model (P=0.01) (Table 3). To assess whether BMI
impacts the relationship between MCP-1 and kidney
function, association analyses were run with participants
stratified as obese (BMI ≥30.0) and non-obese (BMI
<30.0). We found no evidence of an interaction effect
between BMI and MCP-1 on either eGFR or urine ACR. As
shown in Table 6, MCP-1 association parameters in
obese participants were similar to those in the non-obese
group (−0.0004 vs. -0.0004, P=0.75, for the interaction
effect on Log (eGFR); and 0.0017 vs. 0.0013, P=0.68,
for the effect on Log (urine ACR+1)). Evidence of an
association between MCP-1 and kidney function
remained significant in BMI stratified analyses, with
Table 3 MCP-1 associations in the unadjusted and fully adjusted models
MCP-1, monocyte chemoattractant protein-1; HbA1c, hemoglobin A1c; BMI, body mass index; hsCRP, high sensitivity C-reactive protein; CAC, coronary artery
calcified plaque; CarCP, carotid artery calcified plaque; AorCP, infrarenal aorta calcified plaque; ACR, albumin: creatinine ratio; eGFR, estimated glomerular
Adjusted model includes age, sex, smoking, HbA1c, BMI, and LDL-cholesterol.
meta-analysis P-value = 0.001 for Log (eGFR) and 0.04
for Log (urine ACR+1).
Discussion and conclusion
This large cross-sectional study characterized
relationships between serum MCP-1, albuminuria, eGFR and
CP in the understudied AA population with T2D. After
adjusting for covariates, higher serum MCP-1 levels
associated positively with albuminuria and negatively
with eGFR. In contrast, serum MCP-1 did not
independently associate with atherosclerosis and subclinical CVD
measured as CP, suggesting differential molecular
relationships between inflammation, risk for kidney disease,
and CVD in AAs with T2D.
The pathophysiologic connection between
atherosclerosis, CAC, albuminuria and kidney dysfunction is poorly
understood at the molecular level. Previous studies
demonstrated that MCP-1 is involved in the
pathophysiology of atherosclerosis and DN in T1D and T2D [5,7].
MCP-1 is synthesized and secreted by a myriad of cells
(monocytes, macrophages, endothelial cells, renal
mesangial and tubular cells); and both tissue and
systemic cells can contribute to detectable serum MCP-1
levels. In the hyperglycemic milieu, MCP-1 is produced
by resident renal endothelial cells, mesangial cells,
Table 4 Association between MCP-1, eGFR, and ACR in
the fully adjusted model
MCP-1, monocyte chemoattractant protein-1; eGFR, estimated glomerular
filtration rate; ACR, albumin: creatinine ratio.
Covariates included in the model are age, sex, smoking, HbA1c, BMI, and LDL.
podocytes, and tubular epithelial cells; as well as by
circulating or infiltrating monocytes/macrophages .
Several reports attest to the positive correlation between
tissue MCP-1 expression and urine levels with
albuminuria, mesangial proliferation, and interstitial fibrosis in a
wide range of kidney diseases in humans [8,31-36]. In
small studies comprised of European-derived
participants with T1D or T2D, ELISA-based measurements of
serum MCP-1 did not correlate with albuminuria
[30,34]. It has been proposed that while the
histopathology in diabetic kidney disease has remarkable
similarity between type 1 and type 2 diabetes, and between
population groups, the pathogenetic background may
differ between AAs and EAs, and T2D or T1D .
Other longitudinal studies comprised of EAs with T1D,
found that urine MCP-1 levels were significantly higher
in patients with early nephropathy (GFR<90 ml/min and
microalbuminuria) relative to those without
nephropathy, with no difference in serum MCP-1 levels. [18,19]
Relative to EAs, it is possible that inflammatory
pathways are upregulated in AAs. Previous studies have
shown that AAs have higher serum CRP and
interleukin-6 (IL-6) concentrations and display
heightened oxidative stress and inflammation based on
in vitro human umbilical vein endothelial cells
(HUVECs) studies [38,39]. It is biologically plausible that
MCP-1 may play differential roles in the
pathophysiology of DN based on the type of diabetes and ethnic
We originally postulated that inflammation is a
common mediator for both subclinical kidney disease and
CVD in AAs with T2D and that systemic MCP-1 levels
would correlate with markers of kidney disease and
atherosclerosis. We found that a higher burden of vascular
calcification was present in those with albuminuria, but
CP did not associate with serum MCP-1 levels. Other
studies demonstrated that serum MCP-1 levels correlate
with CVD outcomes following acute coronary events,
independent of traditional CVD risk factors .
Nevertheless, these studies did not examine the effect of
serum MCP-1 on CV events based on kidney function
or independent of the association with urine albumin
excretion and eGFR. As in the present report, a large
population-based sample from the Dallas Heart
Study did not observe an association between serum
MCP-1 and CAC after adjusting for age and other
This is the first report of which we are aware detecting
associations between serum MCP-1 with albuminuria
and eGFR in AA patients with T2D and early
nephropathy. Study participants were AAs without advanced
kidney disease and no differences in serum MCP-1 levels
Table 6 Fully adjusted MCP-1 associations stratified by BMI
N Estimate StdErr P-meta P-inter Estimate
BMI < 30.0 134 -0.0004 0.0002 0.001 0.75 0.0017
BMI ≥ 30.0 345 -0.0004 0.0001 0.0013
eGFR, estimated glomerular filtration rate; ACR, albumin: creatinine ratio; BMI, body mass index.
Results were adjusted for age, sex, smoking, HbA1c, and LDL-cholesterol.
eGFR and ACR values were logarithmically transformed.
P-meta is the P-value observed between MCP-1 and each outcome stratified by BMI.
P-inter is the interaction P-value for the association difference between MCP-1 and each outcome in each BMI subgroup.
were seen across genders. The nature of the factors
determining elevated concentrations of serum MCP-1 in
patients with T2D and early DN remains unknown. It is
possible that high MCP-1 expression in the interstitial
kidney macrophages leads to elevated systemic levels of
MCP-1 proportional to the inflammatory and
nephropathy stage. Another possibility, not mutually exclusive, is
that serum MCP-1 levels are elevated in patients with
early nephropathy due to dysregulated activation of
systemic leukocytes. Indeed, several studies confirm an
aberrant production of inflammatory cytokines and
chemokines by circulating lymphocytes and monocytes
in T2D patients with nephropathy . Decreased
filtration of extra-renally synthesized MCP-1 is less likely,
since a minority of participants had an eGFR below
60 ml/min/1.73m .
In addition to roles of MCP-1 in atherosclerosis and
kidney disease, several studies implicated MCP-1 in the
pathophysiology of obesity and insulin resistance [43,44].
In our sample of AAs with T2D, significant correlations
were observed between MCP-1 and BMI, but not with
diabetes duration or HbA1c. The association between
adipose tissue and MCP-1 raised the question whether
the link between serum MCP-1 and renal function
parameters could have been driven by the high prevalence of
obesity in this cohort. Adjustment for BMI and
cholesterol failed to modify the association and BMI-stratified
effect sizes were not statistically different between obese
and non-obese strata. As such, relationships between
serum MCP-1 and kidney function were not impacted
Significant relationships between MCP-1 with eGFR
and albuminuria, coupled with lack of association with
CP, imply that MCP-1 does not mediate joint pathways
implicated in co-existing kidney and CVD. However, the
lack of a cross-sectional association between MCP-1 and
burden of CP in AAs does not exclude a role for this
molecule in the inflammatory component of
atherosclerosis. Previous studies have shown that serum MCP-1
levels are higher in patients with active angina
(compared to those with stable coronary disease), and higher
levels predicted future coronary events and mortality
following an acute coronary event [45,46]. In addition,
serum MCP-1 levels have been associated with
immunohistochemical indices of inflammation and matrix
remodeling in the coronary atherosclerotic plaques of
non-human primates . The role of MCP-1 in CP
should also be explored in EAs, a population with higher
burden of vascular calcification than AAs [12,13].
This study has important strengths and some
limitations. AAs are known to display different patterns of
nephropathy and CVD morbidity relative to EAs. The
large and well phenotyped AA sample enabled
simultaneous evaluation of a molecular biomarker potentially
impacting albuminuria, eGFR, and subclinical
atherosclerosis. Preserved kidney function in AA-DHS
participants lessens concern that altered serum MCP-1 levels
were due to kidney failure, whether mediated by poor
renal excretion or inflammation-driven overproduction.
Limitations include the cross-sectional nature of study
measurements, rendering inability to secure a causal
relationship between MCP-1 and early DN. Longitudinal
studies characterizing relationships between MCP-1 and
albuminuria and eGFR are warranted and could provide
support for pharmacological MCP-1 inhibition during
the incipient stages of DN . Recent studies in mouse
models suggest such treatment has promise .
In conclusion, MCP-1 serum concentrations manifest
positive association with albuminuria and negative
association with eGFR in AAs with T2D; without association
with subclinical atherosclerosis. Relationships between
MCP-1, albuminuria, eGFR, and vascular CP need to be
evaluated in EAs and non-diabetic AAs. MCP-1
inhibition could provide a novel therapeutic strategy to
prevent diabetic kidney disease in AAs with T2D.
HbA1c: Hemoglobin A1c; AA(s): African American(s); AA-DHS: African
American-Diabetes Heart Study; ACEi: Angiotensin-converting enzyme
inhibitor; ACR: Urine albumin: creatinine ratio; AorCP: Infrarenal aorta calcified
plaque; ARB: Angiotensin receptor blocker; BMI: Body mass index; BP: Blood
pressure; CAC: Coronary artery calcified plaque; CarCP: Carotid artery calcified
plaque; CCL2: Chemokine (C-C motif) ligand 2; CKD: Chronic kidney disease;
CKD-EPI: Chronic Kidney Disease Epidemiology; CP: Calcified plaque;
CT: Computed tomography; CVD: Cardiovascular disease; DN: Diabetic
nephropathy; EA(s): European American(s); eGFR: Estimated glomerular
filtration rate; HDL: High density lipoprotein; hsCRP: High sensitivity
Creactive protein; HTN: Hypertension; LDL: Low density lipoprotein;
MCP1: Monocyte chemoattractant protein-1; MDRD: Modification of Diet in Renal
Disease Study; T1D: Type 1 diabetes; T2D: Type 2 diabetes;
The authors report no conflicts of interest.
MM – study design, manuscript preparation; TCR – study design, MCP-1
assays, manuscript preparation; JD – statistical analysis, manuscript editing;
DWB – manuscript editing; JJC – radiologic imaging and interpretation,
manuscript editing; CRH – radiologic imaging interpretation; JX – database
management; CSS – participant recruitment, manuscript editing; CDL –
statistical analysis, manuscript editing; KAH – study design, manuscript
editing; BIF – study design, participant recruitment, supervision of data
analyses, manuscript preparation. All authors read and approved the final
This study was supported in part by the General Clinical Research Center of
the Wake Forest University School of Medicine grant M01 RR07122; and
NIDDK grant RO1 DK071891 (BIF). The investigators acknowledge the
cooperation of our participants and study recruiter Cassandra Bethea. The
authors report no conflicts of interest.
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