Biomarkers of one-carbon metabolism are associated with biomarkers of inflammation in women

Abstract

Folate-mediated one-carbon metabolism is essential for DNA synthesis, repair, and methylation. Perturbations in one-carbon metabolism have been implicated in increased risk of some cancers and may also affect inflammatory processes. We investigated these interrelated pathways to understand their relation. The objective was to explore associations between inflammation and biomarkers of nutritional status and one-carbon metabolism. In a cross-sectional study in 1976 women selected from the Women's Health Initiative Observational Study, plasma vitamin B-6 [pyridoxal-5'-phosphate (PLP)], plasma vitamin B-12, plasma folate, and RBC folate were measured as nutritional biomarkers; serum C-reactive protein (CRP) and serum amyloid A (SAA) were measured as biomarkers of inflammation; and homocysteine and cysteine were measured as integrated biomarkers of one-carbon metabolism. Student's t, chi-square, and Spearman rank correlations, along with multiple linear regressions, were used to explore relations between biomarkers; additionally, we tested stratification by folic acid fortification period and multivitamin use. With the use of univariate analysis, plasma PLP was the only nutritional biomarker that was modestly significantly correlated with serum CRP and SAA (ρ = -0.22 and -0.12, respectively; P < 0.0001). Homocysteine (μmol/L) showed significant inverse correlations with all nutritional biomarkers (ranging from ρ = -0.30 to ρ = -0.46; all P < 0.0001). With the use of multiple linear regression, plasma PLP, RBC folate, homocysteine, and cysteine were identified as independent predictors of CRP; and PLP, vitamin B-12, RBC folate, and homocysteine were identified as predictors of SAA. When stratified by folic acid fortification period, nutrition-homocysteine correlations were generally weaker in the postfortification period, whereas associations between plasma PLP and serum CRP increased. Biomarkers of inflammation are associated with PLP, RBC folate, and homocysteine in women. The connection between the pathways needs to be further investigated and causality established. The trial is registered at clinicaltrials.gov as NCT00000611.

Conflict of interest statement

Author disclosures: C. Abbenhardt, J. W. Miller, X. Song, E. C. Brown, T.-Y. D. Cheng, M. H. Wener, Y. Zheng, A. T. Toriola, M. L. Neuhouser, S. A. A. Beresford, K. W. Makar, L. B. Bailey, D. R. Maneval, R. Green, J. E. Manson, L. Van Horn, and C. M. Ulrich, no conflicts of interest.

Figures

FIGURE 1

Flow chart of the study populations. CRC, colorectal cancer; CRP, C-reactive protein; PLP, pyridoxal-5′-phosphate; SAA, serum amyloid A; WOMIn, Women, One-Carbon Metabolism and Inflammation Study.

FIGURE 2

(A) Pathway analysis in the spring format for nutritional, inflammatory, and integrated biomarkers of one-carbon metabolism. All correlations are partial between each pair of nodes (adjusted for baseline BMI, age). Blue indicates a positive correlation and orange indicates a negative correlation. The weight of the line indicates the strength of the correlation. Pathway analyses for the prefortification (B), perifortification (C), and postfortification (D) periods. B12, plasma vitamin B-12; CRP, serum C-reactive protein; Cys, plasma cysteine; Fol, plasma folate; Hcy, plasma homocysteine; PLP, pyridoxal-5′-phosphate; SAA, serum amyloid A.