The PAr index, an indicator reflecting altered vitamin B-6 homeostasis, is associated with long-term risk of stroke in the general population: the Hordaland Health Study (HUSK)

Hui Zuo, Grethe S Tell, Per M Ueland, Ottar Nygård, Stein E Vollset, Øivind Midttun, Klaus Meyer, Arve Ulvik, Hui Zuo, Grethe S Tell, Per M Ueland, Ottar Nygård, Stein E Vollset, Øivind Midttun, Klaus Meyer, Arve Ulvik

Abstract

Background: Vitamin B-6 homeostasis is altered during inflammation and immune activation. It is unknown whether altered vitamin B-6 homeostasis is associated with the risk of stroke.

Objective: We investigated the relation between the ratio plasma 4-pyridoxic acid: (pyridoxal + pyridoxal-5'-phosphate) (PAr) as an indicator of altered vitamin B-6 homeostasis and the risk of stroke in the general population.

Design: We conducted a prospective analysis of the community-based Hordaland Health Study (HUSK) in 6891 adults (born during 1925-1927 and 1950-1951) without known stroke at baseline (1998-1999). Participants were followed via linkage to the CVDNOR (Cardiovascular Disease in Norway) project and the Cause of Death Registry. HRs and 95% CIs were calculated using Cox proportional hazards analyses.

Results: A total of 390 participants (193 men and 197 women) developed stroke over a median follow-up period of 11 y. Study participants with elevated PAr experienced a higher risk of incident stroke in an essentially linear dose-response fashion. The HR (95% CI) for the highest compared with the lowest quartile of PAr was 1.97 (1.42, 2.73; P-trend <0.001) for total stroke and 2.09 (1.42, 3.09; P-trend <0.001) for ischemic stroke after adjustment for age, sex, body mass index (BMI), smoking, education, physical activity, estimated glomerular filtration rate, hypertension, diabetes, total cholesterol, and statin use. PAr had greater predictive strength than did C-reactive protein, current smoking, diabetes, hypertension, estimated glomerular filtration rate, and physical activity. The associations were similar in subgroups stratified by age group, sex, BMI, current smoking, hypertension, diabetes, and statin use at baseline.

Conclusions: Higher plasma PAr was independently associated with increased risk of incident stroke in all participants and across all subgroups stratified by conventional risk predictors. Our novel findings point to and expand the range of inflammation and immune activation processes that may be relevant for the pathogenesis and prevention of stroke. This trial was registered at clinicaltrials.gov as NCT03013725.

Keywords: biomarker; cohort; inflammation; risk; stroke; vitamin B-6.

© 2018 American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Flow chart of study participants. PA, 4-pyridoxic acid; PAr, 4-pyridoxic acid/(pyridoxal + pyridoxal-5′-phosphate).
FIGURE 2
FIGURE 2
The associations of PAr with total and ischemic stroke by generalized additive models (n = 6891). The models were adjusted for age (46–49 vs. 70–74 y), sex, BMI (continuous), current smoking (yes or no), education (≤10, 11–13, or ≥14 y), physical activity (none/light or moderate/vigorous), eGFR (continuous), hypertension (yes or no), diabetes (yes or no), total cholesterol (continuous), and statin use (yes or no). The solid lines show HRs and the shaded areas 95% CIs. The dashed lines show HRs by linear regression on logarithmic scale. Density plots indicate the distributions of log-transformed PAr, and dotted lines denote the 10th, 50th, and 90th percentiles. eGFR, estimated glomerular filtration rate; PAr, 4-pyridoxic acid/(pyridoxal + pyridoxal-5′-phosphate).

References

    1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, et al. . Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation 2017;135:e146–e603.
    1. Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet 2008;371(9624):1612–23.
    1. Feigin VL, Roth GA, Naghavi M, Parmar PG, Krishnamurthi R, Chugh S, Mensah GA, Norrving B, Shiue I, Ng MY, et al. . Global burden of stroke and risk factors in 188 countries, during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet Neurol 2016;15:913–24.
    1. Bang OY, Ovbiagele B, Kim JS. Nontraditional risk factors for ischemic stroke: an update. Stroke 2015;46:3571–8.
    1. Macrez R, Ali C, Toutirais O, Le Mauff B Defer G, Dirnagl U, Vivien D. Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 2011;10:471–80.
    1. Emerging Risk Factors C, Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010;375(9709):132–40.
    1. Xu T, Ke K. C-reactive protein and ischemic stroke risk in general population: A dose-response meta-analysis of prospective studies. Int J Cardiol 2015;190:264–7.
    1. Zeng X, Zhang G, Yang B, Zhang B, Zhang L, Ni Y, Liu C, Luo Y. Neopterin as a predictor of functional outcome and mortality in Chinese patients with acute ischemic stroke. Mol Neurobiol 2016;53:3939–47.
    1. Lin HS, Tsai TH, Liu CF, Lu CH, Chang WN, Chen SF, Huang CW, Huang CR, Tsai NW, Huang CC, et al. . Serum level and prognostic value of neopterin in patients after ischemic stroke. Clin Biochem 2012;45:1596–601.
    1. Eliot AC, Kirsch JF. Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary considerations. Annu Rev Biochem 2004;73:383–415.
    1. Ueland PM, Ulvik A, Rios-Avila L, Midttun O, Gregory JF. Direct and functional biomarkers of vitamin B6 status. Annu Rev Nutr 2015;35:33–70.
    1. Ueland PM, McCann A, Midttun O, Ulvik A. Inflammation, vitamin B6 and related pathways. Mol Aspects Med 2017;53:10–27.
    1. Ulvik A, Midttun O, Pedersen ER, Eussen SJ, Nygard O, Ueland PM. Evidence for increased catabolism of vitamin B-6 during systemic inflammation. Am J Clin Nutr 2014;100:250–5.
    1. Chiang EP, Smith DE, Selhub J, Dallal G, Wang YC, Roubenoff R. Inflammation causes tissue-specific depletion of vitamin B6. Arthritis Res Ther 2005;7:R1254–62.
    1. Zuo H, Ueland PM, Eussen SJ, Tell GS, Vollset SE, Nygard O, Midttun O, Meyer K, Ulvik A. Markers of vitamin B6 status and metabolism as predictors of incident cancer: the Hordaland Health Study. Int J Cancer 2015;136:2932–9.
    1. Gylling B, Myte R, Schneede J, Hallmans G, Haggstrom J, Johansson I, Ulvik A, Ueland PM, Van Guelpen B Palmqvist R. Vitamin B-6 and colorectal cancer risk: a prospective population-based study using 3 distinct plasma markers of vitamin B-6 status. Am J Clin Nutr 2017;105:897–904.
    1. Ulvik A, Pedersen ER, Svingen GF, McCann A, Midttun O, Nygard O, Ueland PM. Vitamin B-6 catabolism and long-term mortality risk in patients with coronary artery disease. Am J Clin Nutr 2016;103:1417–25.
    1. Vikse BE, Vollset SE, Tell GS, Refsum H, Iversen BM. Distribution and determinants of serum creatinine in the general population: the Hordaland Health Study. Scand J Clin Lab Invest 2004;64:709–22.
    1. Refsum H, Nurk E, Smith AD, Ueland PM, Gjesdal CG, Bjelland I, Tverdal A, Tell GS, Nygard O, Vollset SE. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr 2006;136(6 Suppl):S1731–40.
    1. Midttun O, Hustad S, Ueland PM. Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2009;23:1371–9.
    1. Meyer K, Ueland PM. Targeted quantification of C-reactive protein and cystatin c and its variants by immuno-MALDI-MS. Anal Chem 2014;86:5807–14.
    1. Igland J, Tell GS, Ebbing M, Nygård O, Vollset SE, Dimoski T. Cardiovascular Disease in Norway 1994‐2009 Description of data and data quality. 2013. Internet: accessed Date Accessed).
    1. Sulo G, Igland J, Vollset SE, Nygård O, Øyen N, Tell GS. Cardiovascular disease and diabetes mellitus in Norway during 1994–2009 CVDNOR—a nationwide research project. Nor Epidemiol 2013;23:101–7.
    1. Sulo G, Igland J, Nygard O, Vollset SE, Ebbing M, Tell GS. Favourable trends in incidence of AMI in Norway during 2001–2009 do not include younger adults: a CVDNOR project. Eur J Prev Cardiol 2014;21:1358–64.
    1. Jarvis MJ, Tunstall-Pedoe H, Feyerabend C, Vesey C, Saloojee Y. Comparison of tests used to distinguish smokers from nonsmokers. Am J Pub Health 1987;77:1435–8.
    1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, et al. . Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation 2016;133:e38–360.
    1. American Diabetes Association 2. Classification and diagnosis of diabetes. Diabetes Care 2016;39 Suppl 1:S13–22.
    1. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, et al. . A new equation to estimate glomerular filtration rate. Ann Int Med 2009;150:604–12.
    1. Andersen LF, Solvoll K, Johansson LR, Salminen I, Aro A, Drevon CA. Evaluation of a food frequency questionnaire with weighed records, fatty acids, and alpha-tocopherol in adipose tissue and serum. Am J Epidemiol 1999;150(1):75–87.
    1. Wood SN. Generalized additive models: an introduction with R: Boca Raton: Chapman & Hall/CRC; 2006.
    1. Kuk D, Varadhan R. Model selection in competing risks regression. Statistics in medicine 2013;32(18):3077–88.
    1. Pencina MJ, DʼAgostino RB Sr., D’Agostino RB Jr., Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27:157–72; discussion 207–12.
    1. Pencina MJ, DʼAgostino RB Sr., Steyerberg EW. Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med 2011;30:11–21.
    1. Murray KN, Buggey HF, Denes A, Allan SM. Systemic immune activation shapes stroke outcome. Mol Cell Neurosci 2013;53:14–25.
    1. Fu Y, Liu Q, Anrather J, Shi FD. Immune interventions in stroke. Nat Rev Neurol 2015;11:524–35.
    1. Grimsrud PA, Xie H, Griffin TJ, Bernlohr DA. Oxidative stress and covalent modification of protein with bioactive aldehydes. J Biol Chem 2008;283:21837–41.
    1. Hutcheon JA, Chiolero A, Hanley JA. Random measurement error and regression dilution bias. BMJ 2010;340.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren