(Circulation. 2001;103:2788.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Mass (S.F., P.F.J., I.H.R., J.S.); and Boston University School of Medicine and the National Heart, Lung, and Blood Institutes Framingham Heart Study, Framingham, Mass (P.W.F.W.).
Correspondence to Jacob Selhub, PhD, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111. E-mail jselhub{at}hnrc.tufts.edu
| Abstract |
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Methods and
ResultsData from 891 participants from the
population-based Framingham Heart Study cohort were analyzed.
Subjects were divided into 2 groups according to normal or elevated CRP
values: group 1, CRP <6 mg/L; group 2, CRP
6 mg/L. Plasma PLP levels
were substantially lower in group 2 than in group 1 (mean values in
group 2, 36.5 nmol/L versus 55.8 nmol/L in group 1,
P<0.001). In a multiple
logistic regression model adjusted for tHcy, the association of PLP
with CRP remained highly significant
(P=0.003).
ConclusionsLow plasma PLP is associated with higher CRP levels independently of tHcy. This observation may reflect a vitamin B6 utilization in the presence of an underlying inflammatory process and represent a possible mechanism to explain the decreased vitamin B6 levels in CVD.
Key Words: atherosclerosis risk factors homocysteine vitamins inflammation
| Introduction |
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.3 More evidence
for an inverse correlation between PLP and indices of acute-phase
reaction, such as plasma
1-antichymotrypsin,
copper, and blood leukocyte count, was also recently described in a
sample of elderly
subjects.16 To evaluate the relationship between plasma PLP, the inflammation marker CRP, and tHcy, we analyzed data available from the 20th examination of the Framingham Heart Study, a well-characterized, population-based cohort.
| Methods |
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Additional covariables assessed for the present analyses were age, sex, cigarette smoking, diabetes, history of coronary artery disease, history of CVD, history of stroke events, and history of hypertension. Detailed operational definitions for all these covariables are provided elsewhere.19 20
Laboratory Testing
Samples of venous blood were drawn from each subject
to determine the concentration of CRP, tHcy, folate, vitamin
B12, and PLP. tHcy was determined by
high-performance liquid chromatography with
fluorimetric detection.21
Plasma folate was measured by a microbial assay
(Lactobacillus casei) in a
96-well plate.22 Plasma PLP
was assayed by the tyrosine decarboxylase apoenzyme
method.23 Plasma vitamin
B12 was measured with a (Magic) radioimmunoassay
kit from Ciba-Corning. Serum CRP was determined
by an immunoturbidimetric assay (SPQ antibody
reagent set II, DiaSorin). Creatinine levels were measured
in nonfasting plasma by the Jaffe method, adapted for
autoanalyzers. Dietary vitamin B6 intake
was estimated from diet records by use of a semiquantitative
food-frequency
questionnaire.24
Statistical Analysis
The statistical analyses were confined to a
subset of 891 subjects for whom a complete set of CRP, vitamin, and
tHcy values was available. To evaluate the relationships among plasma
PLP, tHcy, and CRP, we divided the population into 2 groups according
to CRP values: group 1, CRP <6 mg/L, ie, within the range of normality
(n=834, 93.6%); group 2, CRP
6 mg/L, ie, increased levels (n=57,
6.4%). Distributions of continuous variables were expressed as
mean±SD. Logarithmic transformation was performed on all skewed
variables to normalize their distributions. Therefore, geometric
means (antilogarithms of the transformed means) are presented
for tHcy, folate, PLP, vitamin B12,
creatinine, albumin, and dietary vitamin
B6 intake. Ninety-five percent CIs for the
geometric means were calculated by use of the transformed values, and
these intervals are displayed as the antilogarithm of the transformed
data. Adjustment for confounding variables (sex, age, smoking,
albumin, and creatinine) was performed by general
linear model analysis (specifically, ANCOVA) for plasma folate,
plasma PLP, vitamin B12, plasma tHcy,
albumin, and dietary vitamin B6 intake.
Statistical significance refers to a value of
P<0.05. All the statistical
computations were performed with an SAS PROC GLM
program (SAS users guide, version 8.0, SAS Institute,
1999).
| Results |
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6 mg/L, are shown in
Table 1
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| Discussion |
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In a recent study, we also found a negative correlation between PLP and erythrocyte sedimentation rate, disease activity status, disease-related pain, joint swelling, and stiffness in patients with RA (E.-P. Chiang, PhD, et al, unpublished data, 2000). These results were consistent with data from similar studies.3 Furthermore, we demonstrated that the low PLP levels were not due to diminished vitamin B6 intake, nor were they associated with increased urinary excretion of 4-pyridoxic acid, an end product of vitamin B6 catabolism.
Despite the lack of a pathophysiological explanation for an association between PLP and markers of acute-phase status, a plausible interpretation of our data is that PLP is acting as a coenzyme for the inflammation-related functions. Because vitamin B6 is integrally involved in the synthesis of nucleic acids and consequently in mRNA and protein synthesis, the production of cytokines and other polypeptide mediators during the inflammatory response might require an increased utilization of this coenzyme. This model is consistent with the observation that vitamin B6 deficiency is associated with impairment in differentiation and maturation of monocyte-derived macrophages and T lymphocytes, inflammatory cells whose activation leads to the release of several enzymes and cytokines.25 Vitamin B6 deficiency was also reported to alter the regulation of interleukin-2 production.26
The present study, moreover, confirms observations from others of a lack of association of increased CRP and tHcy levels,27 28 suggesting that the relationship between tHcy and atherosclerosis cannot be explained through a link with CRP per se, whereas both are independent risk factors for CVD.
Various conditions such as renal failure, smoking, and age are known to be associated with reduced levels of PLP. In addition, PLP, the predominant form of plasma vitamin B6, is primarily bound to albumin, whose diminished levels may result in lower values of circulating PLP. Adjustment for albumin, creatinine, age, sex, and smoking, however, did not affect the observed association.
Indeed, additional studies are necessary to clarify whether inflammation-associated decreases in circulating PLP play a role in the cascade of metabolic events related to certain diseases. PLP is one of the most important coenzymes in maintaining the balance between protein synthesis and degradation. Therefore, it is likely that low levels of PLP may reflect a higher utilization of the coenzyme in an underlying inflammatory process, rather than a defective intake or excessive vitamin B6 catabolism. The low circulating PLP seen as a possible indicator of an inflammatory status as well as a major determinant of tHcy levels may further our understanding of the mechanisms by which this metabolite acts as a risk factor for CVD.
| Footnotes |
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Received January 29, 2001; revision received March 20, 2001; accepted March 29, 2001.
| References |
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