Associations of Circulating Oxidized LDL and Conventional Biomarkers of Cardiovascular Disease in a Cross-Sectional Study of the Navajo Population
Associations of Circulating Oxidized LDL and Conventional Biomarkers of Cardiovascular Disease in a Cross-Sectional Study of the Navajo Population
Molly E. Harmon 0 1 2
Matthew J. Campen 0 1 2
Curtis Miller 0 1 2
Chris Shuey 0 1 2
Miranda Cajero 0 1 2
Selita Lucas 0 1 2
Bernadette Pacheco 0 1 2
Esther Erdei 0 1 2
Sandy Ramone 0 1 2
Teddy Nez 0 1 2
Johnnye Lewis 0 1 2
0 1 Department of Pharmaceutical Sciences and Community Environmental Health Program, University of New Mexico , Albuquerque , New Mexico, United States of America, 2 Southwest Research and Information Center , Albuquerque, New Mexico , United States of America
1 Funding: This study was funded by the following: HL00773620 National Heart Lung and Blood Institute
2 Editor: Hiroyuki Itabe, Showa University School of Pharmacy , JAPAN
The prevalences of cardiovascular disease (CVD) and type 2 diabetes (T2D) have increased among the Navajo Native American community in recent decades. Oxidized low-density lipoprotein (oxLDL) is a novel CVD biomarker that has never been assessed in the Navajo population. We examined the relationship of oxLDL to conventional CVD and T2D risk factors and biomarkers in a cross-sectional population of Navajo participants. This cross-sectional study included 252 participants from 20 Navajo communities from the Diné Network for Environmental Health Project. Plasma samples were tested for oxLDL levels by a sandwich enzyme-linked immunosorbent assay. Univariate and multivariate analyses were used to determine the relationship of oxLDL and oxidized- to non-oxidized lipoprotein ratios to glycated hemoglobin (HbA1c), C-reactive protein (CRP), interleukin 6 (IL6) and demographic and health variables. Type 2 diabetes, hypertension and obesity are very prevalent in this Navajo population. HbA1c, CRP, body mass index (BMI), high-density lipoprotein, and triglycerides were at levels that may increase risk for CVD and T2D. Median oxLDL level was 47 (36.8-57) U/L. Correlational analysis showed that although oxLDL alone was not associated with HbA1c, oxLDL/HDL, oxLDL/LDL and CRP were significantly associated with HbA1c and glucose. OxLDL, oxLDL/HDL and oxLDL/LDL were significantly associated with CRP. Multivariate analysis showed that triglycerides were a common and strong predictor of oxLDL, oxLDL/HDL and oxLDL/LDL. OxLDL was trended with HbA1c and glucose but did not reach significance, however, HbA1c was an independent predictor of OxLDL/HDL. CRP trended with oxLDL/HDL and was a weak predictor of oxLDL/LDL. This Navajo subset appears to have oxLDL levels comparable to subjects without evidence of CVD reported in other studies. The high prevalence of T2D, hypertension and obesity along with abnormal levels of other biomarkers including HbA1c indicate that the Navajo population has a worsening CVD risk profile.
Data Availability Statement: Data are from the
Dine-Navajo Environmental Health study whose
authors may be contacted at the University of New
Mexico. Data will be made available to interested
researchers pending approval for dissemination of
sensitive data by both the University of New Mexico
Human Research Protections Office and the Navajo
Institutional Review Board.
www.niehs.nih.gov/ JL; ES014565 National Institute
of Environmental Health Sciences, http://www.niehs.
nih.gov/ JL; ES014639 National Institute of
Environmental Health Sciences, http://www.niehs.nih.
gov/ MJC; TR000041 U.S. Environmental Protection
Agency, http://www.epa.gov/ JL and the Center for
Disease Control NIH NCRR M01-RR-00997. The
funders had no role in study design, data collection
and analysis, decision to publish, or preparation of
Competing Interests: The authors have declared
that no competing interests exist.
Abbreviations: CAD, Coronary artery disease; CRP,
C-reactive protein; CVD, Cardiovascular disease;
DiNEH, Diné Network for Environmental Health;
HBA1C, Hemoglobin A1c; HDL, High density
lipoprotein; IL6, Interleukin-6; LDL, Low density
lipoprotein; OxLDL, Oxidized low density lipoprotein;
T2D, Type 2 diabetes; TC, Total cholesterol; TG,
Triglycerides; U.S., United States of America.
Cardiovascular diseases (CVD) and type 2 diabetes (T2D) were rarely reported in the Navajo
population until the 1930s [
]. In recent decades, the prevalences of cardiovascular related
health conditions such as T2D, overweight and hypertension have increased [
], with CVD
being the leading cause of non-accidental death among Navajos [
], as well as in other Native
American populations [
]. It has been well-established that diabetes increases the risk for
CVD, and Navajo are now developing T2D at a rate four times higher than the United States
]. In 1997, the last published comprehensive look at Navajo-specific health status,
the Navajo Health and Nutrition Survey, reported that nearly 40% of Navajos over the age of
45 had T2D [
]. According to a recent Center for Disease Control report, the rate of new T2D
cases among American Indian/Alaskan native youth aged 10–19 is higher than any other
ethnic group or race in the United States (U.S.) [
]. T2D, along with obesity and hypertension,
have become major public health concerns in a population that has become increasingly at risk
Clinically, numerous circulating biomarkers including C-reactive protein (CRP) and
interleukin-6 (IL6) have been useful in predicting CVD outcomes and assessing risk [
has long been established as a marker of chronic systemic inflammation and is regulated by
IL6, a pro-inflammatory cytokine and important inducer and regulator of chronic
]. Novel biomarkers for CVD are emerging including oxidized LDL (oxLDL)
cholesterol. OxLDL is increased in subclinical atherosclerosis [
] and is often a stronger predictor of
acute coronary artery disease (CAD) than standard lipid measures or other conventional risk
]. OxLDL levels are reportedly able to distinguish patients with CAD from healthy
], and serve as a predictor of future myocardial infarction in patients with unstable
]. Oxidized LDL is also associated with T2D [
]. More research is needed to establish
oxLDL as a clinically useful biomarker.
The relationship between oxLDL and CVD risk factors and biomarkers in the Navajo
community is unknown. Given the high prevalence of T2D in this population, our purpose was to
characterize CVD biomarkers in a cross-sectional Navajo population and to evaluate the
association of oxLDL with HbA1C, widely accepted as a major biomarker of glycemic control,
ultimately to better understand how these metrics currently trend in an understudied ethnic
Study Population and Survey Methods
The geographic study area for the study population was located in the northwestern region of
New Mexico, in the political division of the Navajo Nation known as the Eastern Agency.
Demographic and health data were obtained from the Water and Land Use, Environmental
and Health Survey, designed by the Diné Network for Environmental Health (DiNEH) Project
] which implemented a community based participatory approach to enroll 1,304
participants from 20 Chapters of the Navajo Nation. The DiNEH Project was originally intended to
evaluate kidney disease in the Navajo due to potential exposures to uranium from numerous
abandoned uranium mines, but the study was later expanded to evaluate the overall health of
this population, including cardiovascular, immunological and neoplastic diseases. Surveys
were administered by the DiNEH Project in interview fashion to participants between 2005
and 2010. Participants reported CVD related health conditions on the surveys. Height and
weight were measured at the time of survey administration to determine body mass index
(BMI). From these DiNEH participants, we had a recruitment goal for a follow-up blood
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collection of 450 participants; we had a 40–90% recruitment success rate on any given day
from 2010–2011 for a final total of 252 Navajo participants. Non-fasting plasma samples were
collected along with clinical assessments conducted by a Navajo Area Indian Health Service
mobile unit at multiple community locations. All serum biomarker data were derived from this
subset. Blood pressure was measured by automatic cuff. All participants provided written
informed consent, and the study was approved by both the University of New Mexico Human
Research Review Committee and the Navajo Nation Human Research Review Board.
Plasma samples were tested for oxLDL by a sandwich enzyme-linked immunosorbent assay,
according to manufacturer’s instructions (Mercodia, Uppsala, Sweden) (n = 252). The full
volume of intended blood samples was not available for all participants so subsequent analyses
were prioritized resulting in the N noted below for each of the markers reported herein.
Interleukin 6 (IL6) was determined by MILLIPLEX ultrasensitive human magnetic bead set
(Millipore Inc; Billerica, MA) and multiplexing technology to obtain serum cytokine concentration
measures (in pg/ml) (n = 236). Magnetic bead detection was carried out on a MAGPIX
machine and multiplexing platform capable of performing quantitative analysis of low
concentration of protein markers (Luminex Corporation, Austin, TX). Analytical values were
determined by xPONENT 4.2 Software (Luminex Corporation, Austin, TX) by standards provided
in the assay kit for each cytokine. All remaining biochemical analyses were performed by a
reference laboratory (LabCorp, Phoenix, AZ), reported to Indian Health Services and compiled in
a clinical database (RedCAP). Glycated hemoglobin (HbA1c) (n = 249) was determined by the
Roche Tina-quant assay. CRP (n = 249) was assessed quantitatively by latex
immunoturbidimetry. There were 217 samples available for assessing total serum cholesterol, high-density
lipoprotein (HDL), and triglycerides (TG), which were measured by conventional clinical
analytical methods; LDL was measured directly (n = 211).
Descriptive summary statistics were reported as median (interquartile range; IQR) for
continuous variables, unless otherwise indicated. Non-Gaussian distributions were normalized using a
logarithmic transformation. Pearson correlations and multivariate analysis were performed to
assess the relationship of oxLDL to other CVD and T2D risk factors and biomarkers. A value
of P < 0.05 was considered statistically significant. Statistical analyses were performed using R
version 2.12.1 (The R Foundation for Statistical Computing, 2010, 64-bit) and GraphPad
Prism 6.0 (GraphPad Software, La Jolla, CA, USA). All multivariate models were adjusted for
age, gender, BMI, total cholesterol, triglycerides, diastolic and systolic blood pressures,
nonfasting glucose, HbA1c, CRP, and IL6. The model for oxLDL/HDL was also adjusted for LDL
cholesterol, and the oxLDL/LDL model was adjusted for HDL cholesterol. Model selection
was performed based on AIC (Akaike Information Criterion) or BIC (Bayesian Information
Clinical Characteristics and Prevalence of Health Conditions in the
*Biomarker levels and blood pressure were not available for the original DiNEH participants. Data are presented as median (IQR) or %. LDL, low-density
lipoprotein; HDL, high-density lipoprotein; BP, blood pressure; HbA1c, glycated hemoglobin; CRP, C-reactive protein; oxLDL, oxidized low-density
lipoprotein; IL6, interleukin 6.
hypertension were the predominant conditions self-reported by both the subset and original
DiNEH population, at 26.2% (subset) and 25.1% (DiNEH) for diabetes and 38.1% (subset) and
35.9% (DiNEH) for hypertension; heart disease, stroke and myocardial infarction were less
prevalent in both groups.
The prevalence of obesity (BMI 30 kg/m2) in the Navajo subset was 47.6%, which was
higher than the prevalence in the original DiNEH study population (41.2%) (Table 1). Over
one-third of both study populations were overweight (BMI 25.0–29.9 kg/m2). Furthermore, the
majority of participants in both the subset (84.7%) and original DiNEH population (76.2%)
had BMI values considered either “overweight” or “obese.” Only 23% of original DiNEH
participants and 14.5% of the subset were within a normal BMI range (18.5–24.9 kg/m2).
Median systolic blood pressure in the Navajo subset was pre-hypertensive; for 68% of this
study population, systolic pressures were at or above pre-hypertensive levels (>120 mmHg)
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according to American Heart Association guidelines [
] (Table 1). Median diastolic blood
pressure was normal although almost half (47%) of the subset had diastolic pressures that were
measured at or above pre-hypertensive levels (>80 mmHg). Blood pressure measurements
were not available for the original DiNEH population. Thirty-five percent of the subset
reported taking hypertension medication.
Levels of Biomarkers Associated with CVD and T2D
Plasma biomarker levels for the Navajo subset are shown in Table 1. The median oxLDL level
in the Navajo subset was 46.9 (36.8–57) U/L. The median IL6 level was 5.9 (1.8–12.5) pg/ml.
Currently, reference ranges for oxLDL and IL6 as biomarkers have not been established. The
median CRP level was 2.1 (0.9–4.8) (average risk), however, 38.5% had levels greater than 3.0
mg/L, which is considered high risk for heart disease [
]. Circulating lipid levels are shown in
Table 1. Based on American Heart Association guidelines [
] median total cholesterol in this
subset was “desirable,” and LDL cholesterol levels were near optimal. However, HDL
cholesterol was bordering on low, and triglycerides were high; both are risk factors for heart disease.
No data were available for the use of lipid-lowering medications in this subset.
As mentioned, a diagnosis of T2D was self-reported by 26.2% of the Navajo subset (Table 1),
however, our data indicate that 84% of HbA1c levels in the Navajo subset as a whole were
prediabetic (5.7–6.4%) or higher (Table 1, Fig 1), as classified by the American Diabetes Association
]. Indeed, the median HbA1c in the Navajo subset was pre-diabetic at 6.2% (5.8–7.1%).
Furthermore, as shown in Fig 1, of those who denied a diagnosis of diabetes at the time of survey
administration, 59% had pre-diabetic levels of HbA1c with a mean of 6.3% ± 1.3. HbA1c levels
greater than 6.5% are indicative of diabetes. For participants self-reporting a diagnosis of
diabetes, 89% were in the diabetic range with a mean HbA1c of 8.9% ± 2.5. As a whole, more than a
third (39%) of the subset had diabetic levels of HbA1c, and nearly half (46%) were in the
prediabetic range (Table 1). Only 16% were in the normal HbA1c range (<5.6%). The median
nonfasting glucose of this Navajo subset was 91 (78–121) mg/dl (Table 1), which is comparable to a
normal fasting glucose level. Twenty-five percent of the subset reported taking oral medication
and/or insulin for diabetes.
Oxidized LDL Interactions
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Fig 1. Frequency histogram showing survey participants self-reporting a diagnosis of either type 2 diabetes (positive) or no type 2 diabetes
(negative) plotted against participants’ actual HbA1c levels. Dashed lines correspond to HbA1c category cutoffs. Normal: HbA1c 5.6%; Pre-diabetes:
HbA1c = 5.7–6.4%; Diabetes 6.5%.
correlated with TG. OxLDL, oxLDL/HDL and oxLDL/LDL were moderately correlated with
CRP. OxLDL was negatively correlated with IL6. CRP was moderately correlated with IL6.
OxLDL/HDL and CRP were negatively correlated with age. HbA1c and CRP were moderately
correlated BMI. HbA1c was the only biomarker correlated with gender.
Multivariate analysis confirmed that oxLDL was independently and significantly associated
with total cholesterol, LDL and triglycerides but not CRP or IL6. OxLDL was marginally
associated with age, HbA1c and glucose, but these associations did not reach significance (Table 3).
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*Participant self-reported health conditions; heart disease and stroke did not correlate with any biomarkers. Pearson correlation coefficients (r). P < 0.05
was considered statistically significant (bold). Non-Gaussian distributions were log transformed. CVD, cardiovascular disease; oxLDL, oxidized low-density
lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HbA1c, glycated hemoglobin; CRP, C-reactive protein; IL6, interleukin 6, SBP,
systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index
Triglycerides were a very strong predictor of oxLDL/HDL. OxLDL/HDL was independently
and positively associated with HbA1c but negatively associated with glucose. OxLDL/HDL was
weakly and negatively associated with age and total cholesterol and positively associated with
LDL. OxLDL/HDL trended positively with CRP but did not reach significance. OxLDL/LDL
was independently associated with triglycerides and weakly associated with CRP. OxLDL/LDL
was negatively associated with total cholesterol and BMI (Table 3).
Our goal was to measure oxLDL and examine its relationship to health characteristics and T2D
in a cross-sectional subset of the Navajo Nation, as oxLDL has never been assessed in this
population. The median oxLDL level in this subset was 47 U/L (IQR: 36.8–57) and ranged from
12.7–138.2 U/L. The mean oxLDL level (48.5 ± 17.0 U/L) was similar to mean oxLDL levels
measured in subjects without evidence of atherosclerosis reported in other studies [S1 Table;
14, 24–27] that also used the same murine monoclonal antibody 4E6 based ELISA [
However, oxLDL levels varied widely in these studies and consistent associations related to CAD or
diabetes disease status are difficult to discern.
Increased levels of HbA1c, a biomarker for T2D, have been associated with CAD, overall
CVD, and all-cause mortality [
]. For the present Navajo subset, the median HbA1c level
was in the pre-diabetic range with the majority of participants having pre-diabetic (46%) or
diabetic (39%) levels of HbA1c. Other studies have shown an association between oxLDL and
], but in the present study univariate analysis showed that the oxLDL/HDL and
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P < 0.05 was considered statistically significant.
*Non-Gaussian distributions were log transformed.
†Non-fasting. OxLDL, oxidized low-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; BMI, body mass index; SBP, systolic
blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglycerides; HbA1c, glycated hemoglobin; CRP, C-reactive protein; IL6,
oxLDL/LDL ratios correlated significantly with HbA1c, while oxLDL itself correlated only
weakly with HbA1c (p = 0.062). We examined the ratios of oxLDL/HDL and oxLDL/LDL as
previous reports suggest that these metrics may be more informative than oxLDL alone [
]. In a similar study of T2DM, oxLDL/HDL and oxLDL/LDL, but not oxLDL alone, were
associated with atherosclerosis, even when adjusting for BMI, gender, age and hypolipidemic
]. LDL derived from diabetics is more susceptible to oxidation, and this
susceptibility is associated with HbA1c levels [
]. The present Navajo subset also showed a similar
lipid profile as seen in metabolic syndrome/diabetes, wherein LDL is normal, but HDL is low
and triglycerides are high [
]. Thus, although LDL may be lower, it may also be more
susceptible to oxidation further increasing CVD risk in this population.
T2D (26%) and hypertension (38%) in the Navajo subset and original DiNEH population
(25% and 36%, respectively) have increased compared to previous reports [
] and are notably
greater than U.S. prevalences [
]. Overweight and obesity continue to be very prevalent (at
least 76%) in the Navajo population. In the Navajo subset, BMI was moderately correlated with
CRP and HbA1c but not oxLDL or oxidized- to non-oxidized lipoprotein ratios. OxLDL was
correlated with both CRP and IL6, suggesting a potential role for the contribution of overall
inflammation to the health status of this population. CRP was also correlated with oxLDL/
HDL and oxLDL/LDL. The Navajo subset exhibited moderate CRP levels (2.1 mg/dl; IQR: 0.9–
4.8), but over 38% had levels greater than 3.0 mg/dl consistent with increasing risk for CVD.
Mechanistic studies have demonstrated that CRP and oxLDL may be interacting in concert to
promote atherosclerosis [
]. Despite low self-report of heart disease, heart attack and
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stroke, these data suggest that CVD- and T2D-related conditions may become more prevalent
in this middle-aged Navajo population.
It is not surprising that standard lipid measures are predictive overall of oxLDL and oxLDL
ratios with HDL and LDL. Triglycerides in particular were positively associated with all three
response-variables, which is consistent with other studies that have assessed lipid oxidation in
]. HbA1c seems to be somewhat predictive of oxLDL/HDL and perhaps oxLDL
but not oxLDL/LDL. Non-fasting glucose was negatively associated with oxLDL/HDL but
slightly positively associated with oxLDL possibly reflecting more of a post-prandial response.
It has been suggested that LDL oxidation is associated with dyslipidemia as diabetes progresses
]. Although not measured in this study, small dense LDL particles, HDL abnormalities and
diminished serum anti-oxidative capacity in diabetics are strongly associated with metabolic
syndrome and diabetes [
]. Inflammation is a component of both atherogenesis and
the development of diabetes. CRP was somewhat predictive of the oxLDL ratios with HDL and
LDL but not of oxLDL itself. Age was negatively associated with oxLDL and oxLDL/HDL
suggesting that these variables decrease in middle age in the Navajo population. OxLDL/HDL
appears to be higher in women.
An important limitation of our study was that some plasma obtained for biomarker
assessments (2010–2011) was collected at the end of the survey administration (2005–2010). Thus,
subjects may not have initially reported health conditions for which they were later diagnosed.
Although review of medical records was attempted, complete records were not available for all
volunteers so not all self-reported health conditions could be validated. Navajo also engage in
traditional medical practices, which would not be included in clinical medical records.
However, for the self-reported measures of BMI (data not shown) and diabetes where sufficient
clinical data were available at the time of blood collection, concordance with self-report was >80%
with errors. Thus, given that the time between survey and clinical assessment could range as
long as 5 years, observed discrepancies were consistent with a clinical finding of disease
subsequent to the survey. Although bias may present due to self-selection, the Navajo subset was
similar to the larger DiNEH study population based on age, gender, BMI and self-reported
disease conditions. Non-fasting blood samples may impact some of the biomarker levels, however,
non-fasting lipid levels may better predict risk of cardiovascular events [
]. Participant use of
diabetic and hypertensive medications was not included in our initial analysis.
The cross-sectional nature of this study does not allow for the determination of causality.
The results of this study cannot be generalized to other populations. Finally, this population is
known to have significant environmental exposure risks to metals from the legacy of uranium
mining. However, the study population reported herein spans the full range of those exposures,
including a significant proportion of unexposed participants [
], improving the
generalizability of our results.
The Navajo population faces a dramatic increase in overall CVD risk profile. This population
is greatly in need of better control of diabetes, hypertension and obesity to prevent future
CVD-related health complications. Concentrations of the CVD marker oxLDL in the Navajo
population trend with indices of metabolic syndrome and T2D, but were consistent with
several other published cohorts. The relationship between oxLDL and absolute CVD risk in
individuals with pre-diabetes and diabetes from this underserved ethnic group remains unclear.
Ongoing and future analyses are exploring the potential role of chronic environmental
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exposures and other possible socioeconomic and lifestyle risk factors in contributing to
S1 Table. Comparison of Navajo subset mean oxLDL levels, age, BMI, and HbA1c and/or
diabetes status with other studies using monoclonal antibody 4E6 to measure circulating
The authors wish to sincerely thank all Navajo chapter members who participated in this
Conceived and designed the experiments: MEH MJC. Performed the experiments: MEH EE.
Analyzed the data: MEH MJC CM. Contributed reagents/materials/analysis tools: MJC EE JL.
Wrote the paper: MEH MJC. Executed bioassays, analyzed data, and wrote most of the paper:
MEH. Developed the concept for exploring oxidized LDL as a marker, assisted with data
analysis and authorship and helped fund aspects of the study: MJC. Provided statistical expertise:
CM. Facilitated interactions with the study population and aided in the culturally-sensitive
design of the health study: CS. Helped with collecting biological sampling and database
management: MC. Helped with collecting biological sampling and study conduct: SL BP. Helped in
the design of the health outcomes study and analyzed samples for IL6: EE. Helped with
collecting biological sampling and interfacing with the community: SR TN. Conceived/designed the
overall health outcomes study and provided funding and leadership for its execution: JL.
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