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VOLUME 9 NUMBER 2 • JUNE 2012
RESEARCH ARTICLE
SA JOURNAL OF DIABETES & VASCULAR DISEASE
is poorly understood. In the present study we found IgG anti-
oxLDL antibodies to be low in individuals with hyperglycaemia,
especially in those with undiagnosed diabetes, perhaps due to
the unmanaged glycaemic state. Furthermore, after the multiple
stepwise linear regression analysis, two-hour post blood glucose
showed a negative association with anti-oxLDL antibodies.
Although there are several reports on the levels of anti-
oxLDL antibodies in patients with diabetes, there is considerable
inconsistency in reports from several investigators. In a longitudinal
study, Garrido-Sánchez
et al.
17
demonstrated that low levels of anti-
oxLDL antibodies in subjects with normal glucose tolerance, impaired
fasting glucose or impaired glucose tolerance were a significant
predictor of onset of type 2 diabetes. Furthermore, another report
had previously shown a distinct fall of these antibodies after the
age of 35 years,
22
and increasing age is strongly associated with the
development of type 2 diabetes. By contrast, other studies have
found higher,
11,23
or comparable levels of anti-oxLDL antibodies in
both type 1 and type 2 diabetes.
24-26
Anti-oxidised LDL antibodies have been found in patients with
advanced atherosclerotic lesions,
27
however, their role in atherosclerosis
is also controversial. Salonen
et al
.
15
reported high levels of auto-
antibodies to malonyldialdehyde-LDL particles in subjects with carotid
atherosclerosis, but the Framingham Offspring study failed to show a
relationship between baseline levels of IgG anti-oxLDL antibodies and
the development of CVD or coronary heart disease.
28
Furthermore,
another study found an inverse relationship between antibody levels
and carotid intima–media thickness after adjusting for several CVD risk
factors such as age, blood pressure, BMI and lipid levels.
29
We also observed a negative association with cardiovascular
disease risk factors, as shown by the inverse association between
anti-oxLDL antibodies and several markers of cardiovascular disease.
After multiple stepwise linear regression, an increase in levels of
total cholesterol and triglycerides and age was associated with a
reduction in the levels of anti-oxLDL antibodies.
Standard CVD risk factors such as male gender, age, obesity, high
blood pressure, diabetes mellitus, and total and HDL cholesterol
levels are well established and have been used in the CVD interactive
risk calculator.
21
We also used the CVD risk calculator and found
that, in keeping with the strong link between hyperglycaemia
and CVD risk, the CVD risk scores were significantly higher in
subjects with hyperglycaemia. Furthermore, HbA
1c
and hs-CRP
levels correlated negatively with anti-oxLDL antibodies. Similarly,
Santos and co-workers
30
showed a negative correlation between
anti-oxLDL antibodies and hs-CRP levels, and an inverse association
after performing a multiple linear regression analysis.
CRP and HbA
1c
have recently gained popularity in the assessment
of cardiovascular disease risk. However, the range of CRP levels
associated with vascular risk is way below the reference range used
to assess inflammation, and high sensitivity assays were developed
to measure CRP levels associated with CVD risk.
31
Recent prospective
studies have shown that elevated HbA
1c
levels are associated
with risk of CVD and death.
32
This association has recently been
extended to non-diabetic subjects, where non-diabetic adults with
HbA
1c
levels of 6.0% or higher were found to be at an increased
risk of developing CVD and diabetes mellitus.
32
It has been suggested that measurement of level of antibodies
against oxLDL may serve as an index of
in vivo
LDL oxidation,
however this remains to be elucidated. While lipoprotein oxidation
was not measured in the present study, serum cotinine levels,
which are a reliable marker of tobacco exposure,
33
demonstrated
an inverse association with anti-oxLDL antibody levels. Cigarette
smoking exposes an individual to a variety of highly oxidant gases
and free radicals, and is believed to add to the toxic accumulation
of reactive oxygen species (ROS) in the diabetic subject.
34
Therefore our results partially support the role of these antibodies
as an indirect assessment of oxidation, whereby lower antibody
levels may indicate increased oxidative stress with a consequent
increase in LDL oxidation. It is however pertinent to mention that
waist circumference was retained after multiple stepwise linear
regression analysis and showed a positive association with anti-
oxLDL antibody levels. Although obesity is defined by body mass
index, it is central obesity as measured by the waist circumference
that is strongly associated with metabolic abnormalities.
Adipose tissue expresses inflammatory cytokines, interleukin-6
(IL-6) and tumour necrosis factor-
a
(TNF-
a
), which are a source
of oxidative stress.
35
A relationship between abdominal fat and
enhanced lipid peroxidation has been demonstrated by the direct
proportional elevation of oxidative stress biomarkers, particularly
oxidised LDL (OxLDL) and waist circumference.
36
The discrepancy between the role of antibodies against oxidised
LDL reported in this study and that in other studies could be due to
the heterogeneous effect of these antibodies. Human IgG antibodies
have different subclasses, including IgA, IgG1, IgG2 and IgG3.
37
While
IgG2 is the dominant subclass to respond to epitopes containing
phospholipids, it is the IgG3 subclass that is more pathogenic as it
fixes complement better and binds Fc receptors more ardently.
38
The major limitation in this study was the measurement of total
IgG anti-oxLDL antibodies, as quantification of the specific antibody
subclasses may elucidate the role and usefulness of these antibodies
in various disease states. Another limitation was the inclusion of only
one ethnic group, the mixed-ancestry population of South Africa,
with a reportedly high incidence of diabetes.
39
These anti-oxLDL
antibodies have been shown to differ in south Asian individuals with
an increased risk of atherosclerosis compared to whites.
40
Conclusion
Our findings demonstrated that anti-oxLDL antibody levels were
reduced in subjects with hyperglycaemia and that these low levels
were associated with an increased cardiovascular disease risk score.
However, these findings should be corroborated by further studies,
taking into account the different subclasses of human IgG anti-
oxLDL antibodies, as well as different ethnic groups. Furthermore,
future studies should compare individuals with cardiovascular
disease but with normal glucose tolerance to individuals with
coronary artery disease and abnormal glucose tolerance, in order
to determine whether reduced anti-oxLDL levels are a risk factor for
cardiovascular diseases.
Acknowledgements
This research was supported by a grant from the University Research
Fund of the Cape Peninsula University of Technology, South Africa.
The grant was used solely for funding the project. We thank the
Bellville South community for participating in this study.
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