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Independent and Synergistic Associations of Biomarkers of Vitamin D Status With Risk of Coronary Heart Disease (article)
Arterioscler Thromb Vasc Biol. 2017 Nov;37(11):2204-2212. doi: 10.1161/ATVBAHA.117.309548. Epub 2017 Sep 7.
Most previous Cardio studies focused only on Vitamin D test results, not VDBP
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- Overview Stroke and vitamin D
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Items in both categories Cardiovascular and DBP listed here:
- Coronary Artery Disease risk both increased and decreased by 30 percent with mutations in Vitamin D Binding – April 2016
- Coronary Heart Disease 57 percent more likely if poor Vitamin D Binding Protein with high PTH – Nov 2017
- Vitamin D Binding Protein and Coronary artery disease – Oct 2017
- Heart Disease 40 percent more likely in women having poor Vitamin D Binding Protein – Sept 2017
Qi L1, Ma W2, Heianza Y2, Zheng Y2, Wang T2, Sun D2, Rimm EB2, Hu FB2, Giovannucci E2, Albert CM2, Rexrode KM2, Manson JE1.
- 1 From the Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA (L.Q., Y.H., T.W., D.S.); Department of Epidemiology (L.Q., W.M., E.B.R., F.B.H., E.G., J.E.M.) and Department of Nutrition (L.Q., Y.Z., E.B.R., F.B.H., E.G.), Harvard T.H. Chan School of Public Health, Boston, MA; and Channing Division of Network Medicine (L.Q., E.B.R., F.B.H., E.G., J.E.M.) and Division of Preventive Medicine (C.M.A., K.M.R., J.E.M.), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. lqil at tulane.edu jmanson at rics.bwh.harvard.edu.
- 2 From the Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA (L.Q., Y.H., T.W., D.S.); Department of Epidemiology (L.Q., W.M., E.B.R., F.B.H., E.G., J.E.M.) and Department of Nutrition (L.Q., Y.Z., E.B.R., F.B.H., E.G.), Harvard T.H. Chan School of Public Health, Boston, MA; and Channing Division of Network Medicine (L.Q., E.B.R., F.B.H., E.G., J.E.M.) and Division of Preventive Medicine (C.M.A., K.M.R., J.E.M.), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
To comprehensively evaluate the independent associations and potential interactions of vitamin D-related biomarkers including total and bioavailable 25-hydroxyvitamin D (25OHD), VDBP (vitamin D binding protein), and parathyroid hormone (PTH) with risk of coronary heart disease (CHD).
APPROACH AND RESULTS:
We prospectively identified incident cases of nonfatal myocardial infarction and fatal CHD among women in the Nurses' Health Study during 20 years of follow-up (1990-2010). Using risk-set sampling, 1 to 2 matched controls were selected for each case. The analysis of 25OHD and PTH included 382 cases and 575 controls; the analysis of VDBP included 396 cases and 398 controls. After multivariate adjustment, plasma levels of total 25OHD, bioavailable 25OHD, and PTH were not significantly associated with CHD risk.
VDBP was associated with a lower CHD risk with an extreme-quartile odds ratio of 0.60 (95% confidence interval, 0.39-0.92; P trend=0.02). When examining the biomarkers jointly, a significant, inverse association between 25OHD and CHD was observed among participants with higher PTH levels (P for interaction=0.02). The odds ratio (95% confidence interval) comparing the highest quartile of 25OHD to lowest was 0.43 (0.23-0.82; P trend=0.003) when PTH levels were above population median (35.3 pg/mL), whereas among the rest of participants the corresponding odds ratio (95% confidence interval) was 1.28 (0.70-2.36; P trend=0.43).
Our data suggest that higher 25OHD levels were associated with a lower CHD risk when PTH levels were high, whereas no association was observed for participants with low PTH levels. VDBP but not bioavailable 25OHD was independently associated with lower CHD risk.
PMID: 28882871 PMCID: PMC5658253 [Available free on 2018-11-01] DOI: 10.1161/ATVBAHA.117.309548
Vitamin D and Risk of Cardiovascular Disease – Editorial, same issue
Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37:1981-1982. published October 25, 2017
Shoaib Afzal, Børge G. Nordestgaard, https://doi.org/10.1161/ATVBAHA.117.310204
Observational studies have mostly found a strong association of low plasma 25-hydroxyvitamin D (25(OH)D), usually used to measure vitamin D status, with increased risk of coronary heart disease, stroke, and cardiovascular death.1–3 However, recent Mendelian randomization studies and randomized intervention trials do not support a causal association of 25(OH)D or vitamin D supplementation with cardiovascular disease. 4–8 This discrepancy has been ascribed to failures to account either for confounding or reverse causation in observational studies or for the nonlinear relationships in genetic studies and inappropriate recruiting of vitamin D replete individuals to vitamin D supplementation trials.
See accompanying article on page 2204
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Qi et al 9 present a comprehensive report on the association of 25(OH)D and other biomarkers of vitamin D status on coronary heart disease. Using the Nurses’ Health Study in a nested case–control design with 382 cases and 575 controls and 20-year follow-up, they show independent associations of VDBP (vitamin D–binding protein) with coronary heart disease and an interaction of 25(OH)D with parathyroid hormone on risk of coronary heart disease (Figure). However, 25(OH)D was not independently associated with coronary heart disease. In essence, this report claims that reality may be more complex than claiming that low 25(OH)D is a risk factor for coronary disease (Figure). The main limitation of these findings is that this is an observational study that cannot escape residual confounding; therefore, causal claims cannot be substantiated beyond reference to biological plausibility. Other limitations include the modest sample size and the relatively high mean levels of 25(OH)D in the population studied. In addition, there are no immediate consequences for clinical practice. Nevertheless, this study also underlines the strengths of observational studies: the ease, with which complex hypotheses can be tested, and generation of new testable hypotheses that may be evaluated in superior designs to improve clinical practice.
Proposed models for the association of biomarkers of vitamin D status with risk of coronary disease. 25(OH)D indicates 25-hydroxyvitamin D; PTH, parathyroid hormone; and VDBP, vitamin D–binding protein.
This study 9 adds to the growing literature indicating that biomarkers of vitamin D status beyond 25(OH)D may have an independent role in cardiovascular disease. Previous studies have shown that VDBP is a carrier for actin, and VDBP may be important in regulation of inflammatory responses. Inflammation has been shown to be important in causing coronary heart disease,10 and in experimental studies, actin metabolism has also been linked to cardiovascular disease. 11,12 Such data indicate that VDBP could be a confounder in the association of 25(OH)D with coronary heart disease. However, several large studies, using genetic variants in VDBP that are associated with VDBP levels,13 have failed to show an association with cardiovascular end points, decreasing the enthusiasm for pursuing this as a potential therapeutic target.14–17 Furthermore, genetic variants associated with VDBP levels have been present on arrays (metabochip and exome chip) used in large consortia investigating cardiovascular disease but have not shown up as a hit in any of them. In contrast, the interaction of 25(OH)D with parathyroid hormone has been sparsely investigated. Despite the number of statistical comparisons presented in the modestly sized case–control study by Qi et al, we think, as the authors also state, that this question deserves further investigation because the present results cannot be interpreted as being decisive.
In conclusion, the study by Qi et al highlights that other biomarkers of vitamin D status could be independently associated with risk of coronary heart disease and that there could be potential interactions of the biomarkers with regard to risk of coronary heart disease. Further studies are needed to investigate these hypotheses and any potential consequences for clinical practice.
Most importantly, we are all awaiting the randomized intervention of vitamin D supplementation to be published in the near future (eg,
- ViDA [The Vitamin D Assessment],
- CAPS [Clinical Trial of Vitamin D3 to Reduce Cancer Risk in Postmenopausal Women],
- VITAL [Vitamin D and Omega-3 Trial],
- DO-HEALTH [Vitamin D3 - Omega3 - Home Exercise - Healthy Ageing and Longevity Trial], and
- FIND [Finnish Vitamin D Trial]).8,18
These randomized trials will provide us with definitive answers as to whether vitamin D supplementation will reduce cardiovascular disease or not and whether vitamin D is causally related to cardiovascular disease.
References (for Editorial)
- 1.↵Brøndum-Jacobsen P, Benn M, Jensen GB, Nordestgaard BG. 25-Hydroxyvitamin d levels and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and meta-analyses of 18 and 17 studies. Arterioscler Thromb Vasc Biol. 2012;32:2794–2802. doi: 10.1161/ATVBAHA.112.248039.Abstract/FREE Full TextGoogle Scholar
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- 7.↵Brøndum-Jacobsen P, Benn M, Afzal S, Nordestgaard BG. No evidence that genetically reduced 25-hydroxyvitamin D is associated with increased risk of ischaemic heart disease or myocardial infarction: a Mendelian randomization study. Int J Epidemiol. 2015;44:651–661. doi: 10.1093/ije/dyv078.CrossRefPubMedGoogle Scholar
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- 9.↵Qi L, Ma W, Heianza Y, Zheng Y, Wang T, Sun D, Rimm EB, Hu FB, Giovannucci E, Albert CM, Rexrode KM, Manson JE. Independent and synergistic associations of biomarkers of vitamin D status with risk of coronary heart disease. Arterioscler Thromb Vasc Biol. 2017;37:2204–2212. doi: 10.1161/ATVBAHA.117.309548.Abstract/FREE Full TextGoogle Scholar
- 10.↵Ridker PM, Everett BM, Thuren T, et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131. doi: 10.1056/NEJMoa1707914.Google Scholar
- 11.↵Erukhimov JA, Tang ZL, Johnson BA, Donahoe MP, Razzack JA, Gibson KF, Lee WM, Wasserloos KJ, Watkins SA, Pitt BR. Actin-containing sera from patients with adult respiratory distress syndrome are toxic to sheep pulmonary endothelial cells. Am J Respir Crit Care Med. 2000;162:288–294. doi: 10.1164/ajrccm.162.1.9806088.CrossRefPubMedGoogle Scholar
- 12.↵Haddad JG, Harper KD, Guoth M, Pietra GG, Sanger JW. Angiopathic consequences of saturating the plasma scavenger system for actin. Proc Natl Acad Sci USA. 1990;87:1381–1385.Abstract/FREE Full TextGoogle Scholar
- 13.↵Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010;376:180–188. doi: 10.1016/S0140-6736(10)60588-0.CrossRefPubMedGoogle Scholar
- 14.↵Kunutsor SK, Burgess S, Munroe PB, Khan H. Vitamin D and high blood pressure: causal association or epiphenomenon? Eur J Epidemiol. 2014;29:1–14. doi: 10.1007/s10654-013-9874-z.CrossRefPubMedGoogle Scholar
- 15.↵Leong A, Rehman W, Dastani Z, Greenwood C, Timpson N, Langsetmo L, Berger C, Fu L, Wong BY, Malik S, Malik R, Hanley DA, Cole DE, Goltzman D, Richards JB; METASTROKE. The causal effect of vitamin D binding protein (DBP) levels on calcemic and cardiometabolic diseases: a Mendelian randomization study. PLoS Med. 2014;11:e1001751. doi: 10.1371/journal.pmed.1001751.CrossRefPubMedGoogle Scholar
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- 16.↵Manousaki D, Mokry LE, Ross S, Goltzman D, Richards JB. Mendelian randomization studies do not support a role for vitamin D in coronary artery disease. Circ Cardiovasc Genet. 2016;9:349–356. doi: 10.1161/CIRCGENETICS.116.001396.Abstract/FREE Full TextGoogle Scholar
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Coronary Heart Disease Events 2.4 X more likely in Chinese if poor VDBP - Aug 2017
Associations of Vitamin D-Binding Globulin and Bioavailable Vitamin D Concentrations With Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA).
J Clin Endocrinol Metab. 2017 Aug 1;102(8):3075-3084. doi: 10.1210/jc.2017-00296.
Robinson-Cohen C1, Zelnick LR1, Hoofnagle AN2, Lutsey PL3, Burke G4, Michos ED5,6, Shea SJC7,8, Tracy R9,10, Siscovick DS11, Psaty B12,13,14, Kestenbaum B1, de Boer IH1.
CONTEXT: Low 25-hydroxyvitamin D [25(OH)D] is associated with coronary heart disease (CHD) in people who are white and Chinese but not black or Hispanic. Vitamin D binding globulin (VDBG) avidly binds 25(OH)D, reducing its bioavailability, and differs in isoform and concentration by race.
OBJECTIVE: Evaluate associations of VDBG with CHD and whether accounting for VDBG or estimating bioavailable 25(OH)D explains the heterogeneity of the association of 25(OH)D with CHD.
DESIGN AND SETTING:
We conducted a case-cohort study within the Multi-Ethnic Study of Atherosclerosis. Participants with an incident CHD event over 12 years of follow-up (n = 538) and a randomly assigned subcohort (n = 999) were included. We measured baseline 25(OH)D, VDBG, and isoforms using mass spectrometry and estimated bioavailable 25(OH)D from published equations.
VDBG was associated with an increased risk of CHD [hazard ratio, 1.77 (95% confidence interval, 1.46 to 2.14) per standard deviation increment, P < 0.0001], without evidence of heterogeneity by race or isoform (each P for interaction > 0.1). Low total 25(OH)D was differentially associated with CHD events, by race, with or without adjustment for VDBG (P for interaction = 0.04 or 0.05, respectively). Associations of 25(OH)D with CHD were strengthened with adjustment for VDBG among participants who were white or Chinese, and bioavailable 25(OH)D was associated with CHD events only among white participants.
High VDBG concentration was associated with CHD events in all racial and ethnic groups. Incorporation of VDBG strengthened existing associations of 25(OH)D with CHD but did not explain racial heterogeneity in associations of 25(OH)D with CHD.
PMID: 28472285 PMCID: PMC5546864 DOI: 10.1210/jc.2017-00296
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