Pathophysiological Consequences of Protein N-Homocysteinylation - Homocysteine in Protein Structure/Function and Human Disease - page 110

with Hcy [64, 73, 74] and in vivo in hyperhomocysteinemia due to CBS-, MTHFR-,
or PCFT-deficiency in humans [115] and mice [113], triggers an autoimmune
response.

6.2.4 Anti- N -Hcy-Protein Autoantibodies in Atherosclerosis

Plasma levels of anti-N-Hcy-protein autoantibodies, similar to plasma tHcy levels,
are significantly elevated in stroke and CAD patients. For example, 63-year-old
male stroke patients (n ¼ 37) have higher serum levels of tHcy and anti-N-Hcy-

protein autoantibodies, compared with age-matched control individuals (n ¼

29)

[172]. However, in groups of women stroke patients (n ¼ 17) and control

individuals (n ¼ 45), in whom tHcy levels are similar, the levels of anti-N-Hcy-

protein autoantibodies are also similar.
In a larger study of patients 50 years old, the seropositivity to anti-N-Hcy-

protein autoantibodies is fivefold more frequent in male patients (n ¼

<

88) with
angiographically confirmed CAD than in age-matched healthy individuals
(n ¼ 0.001) [135]. To examine the clinical usefulness

of anti-N-Hcy-protein IgG autoantibodies, their predictive value in CAD is
analyzed and compared to the predictive value of tHcy and other risk factors
[135]. An age-adjusted risk for early CAD in men

100) (52 % vs. 10 %, P <

50 years old, related to
seropositivity for anti-N-Hcy-protein IgG autoantibodies,

<

is 9.87 (95 % CI

10 5 ). In multivariate logistic regression analysis, only seroposi-
tivity to anti-N-Hcy-protein IgG autoantibodies (OR 14.92; 95 % CI 4.47-49.19;
p ¼

4.50-21.59, p <

0.001), hypertension
(OR 43.45; 95 % CI 7.91-238.7), and HDL cholesterol (OR 0.015; 95 % CI
0.002-0.098; p ¼

0.00002), smoking (OR 8.84; 95 % CI 2.46-31.72; p ¼

0.00002) are independent predictors of early CAD. Interestingly,
compared with tHcy, anti-N-Hcy-protein IgG autoantibodies are a more sensitive
predictor of early CAD in men. A risk for premature CAD is almost 15-fold higher
in patients who are seropositive for anti-N-Hcy-protein IgG autoantibodies after
adjusting for coronary risk factors, Hcy and CRP. These analyses show that
elevated levels of anti-N-Hcy-protein autoantibodies significantly contribute to
the risk of CAD in male patients [135]. Taken together, these studies suggest that
an autoimmune response against N-Hcy-proteins is a feature of Hcy-linked athero-
sclerosis [69, 134].
The findings that the levels of N-Hcy-protein are elevated in uremic patients on
hemodialysis [300, 301] suggest that an autoimmune response against N-Hcy-
protein might also be enhanced in these patients. This possibility was examined
in a group of 43 patients (58.8 years old) who were on maintenance hemodialysis
for an average of 50 months and an age- and sex-matched group of 31 apparently
healthy individuals [379]. Significantly higher levels of anti-N-Hcy-protein IgG
autoantibodies are found in the hemodialysis patients, compared with controls.
Similar to the studies with stroke patients [172], the levels of anti-N-Hcy-protein
IgG autoantibodies are strongly correlated with plasma tHcy, both in hemodialysis