Cardiovascular disease outcomes in relation to 25-hydroxyvitamin D and its seasonal variation: Results from the BiomarCaRE consortium

Viktor Oskarsson; Veikko Salomaa; Pekka Jousilahti; Luigi Palmieri; Chiara Donfrancesco; Susana Sans; Licia Iacoviello; Simona Costanzo; Marco M. Ferrario; Giancarlo Cesana; Barbara Thorand; Annette Peters; Hugh Tunstall-Pedoe; Mark Woodward; Tanja Zeller; Stefan Blankenberg; Kari Kuulasmaa; Stefan Söderberg

doi:10.1371/journal.pone.0319607

Cardiovascular disease outcomes in relation to 25-hydroxyvitamin D and its seasonal variation: Results from the BiomarCaRE consortium

Viktor Oskarsson (Lead / Corresponding author), Veikko Salomaa, Pekka Jousilahti, Luigi Palmieri, Chiara Donfrancesco, Susana Sans, Licia Iacoviello, Simona Costanzo, Marco M. Ferrario, Giancarlo Cesana, Barbara Thorand, Annette Peters, Hugh Tunstall-Pedoe, Mark Woodward, Tanja Zeller, Stefan Blankenberg, Kari Kuulasmaa, Stefan Söderberg

Cardiovascular Research

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Abstract

Background It has been hypothesized but seldom tested that the winter excess in cardiovascular disease (CVD) is related to hypovitaminosis D. The present study examined the association between CVD and (i) seasonality of 25-hydroxyvitamin D (25[OH]D) and (ii) individual 25(OH)D concentrations. Methods and findings Harmonized 25(OH)D data were obtained from the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, including 79,570 participants examined between 1984 and 2010. One 25(OH)D measurement was available per participant. Primary endpoints were CVD incidence (coronary heart disease or stroke; n = 6006) and CVD mortality (n = 2985). To study (i), Poisson regression-derived rate ratios were compared according to two-month categories, ordered by baseline 25(OH)D concentrations. To study (ii), Cox regression-derived hazard ratios were compared according to quarters of baseline 25(OH)D concentrations. With respect to (i), despite a median 25(OH)D concentration ratio of 1:1.79, the trough months of 25(OH)D in March and April had a similar CVD incidence as the peak months of 25(OH)D in August and September (rate ratio: 1.07, 95% CI: 0.98–1.17). CVD mortality was slightly higher in the trough months compared to the peak months (rate ratio: 1.27, 95% CI: 1.12–1.44) but not compared to the other months (despite median 25[OH]D concentration ratios up to 1:1.62; p ≥ 0.077). The CVD mortality peak in January preceded the 25(OH)D trough, not adhering to the temporality criterion of Bradford Hill. With respect to (ii), compared to the lowest quarter, the highest quarter of 25(OH)D was associated with lower CVD incidence (hazard ratio: 0.82, 95% CI: 0.76–0.89) and CVD mortality (hazard ratio: 0.64, 95% CI: 0.57–0.72). Conclusion The present study does not support the hypothesis that seasonal increases in CVD are driven by short-term reductions in 25(OH)D. As in most observational studies, higher 25(OH)D concentrations were inversely associated with CVD.

Original language	English
Article number	e0319607
Number of pages	18
Journal	PLoS ONE
Volume	20
Issue number	4 April
Early online date	24 Apr 2025
DOIs	https://doi.org/10.1371/journal.pone.0319607
Publication status	E-pub ahead of print - 24 Apr 2025

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Copyright: © 2025 Oskarsson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Oskarsson, V., Salomaa, V., Jousilahti, P., Palmieri, L., Donfrancesco, C., Sans, S., Iacoviello, L., Costanzo, S., Ferrario, M. M., Cesana, G., Thorand, B., Peters, A., Tunstall-Pedoe, H., Woodward, M., Zeller, T., Blankenberg, S., Kuulasmaa, K., & Söderberg, S. (2025). Cardiovascular disease outcomes in relation to 25-hydroxyvitamin D and its seasonal variation: Results from the BiomarCaRE consortium. PLoS ONE, 20(4 April), Article e0319607. Advance online publication. https://doi.org/10.1371/journal.pone.0319607

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title = "Cardiovascular disease outcomes in relation to 25-hydroxyvitamin D and its seasonal variation: Results from the BiomarCaRE consortium",

abstract = "Background It has been hypothesized but seldom tested that the winter excess in cardiovascular disease (CVD) is related to hypovitaminosis D. The present study examined the association between CVD and (i) seasonality of 25-hydroxyvitamin D (25[OH]D) and (ii) individual 25(OH)D concentrations. Methods and findings Harmonized 25(OH)D data were obtained from the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, including 79,570 participants examined between 1984 and 2010. One 25(OH)D measurement was available per participant. Primary endpoints were CVD incidence (coronary heart disease or stroke; n = 6006) and CVD mortality (n = 2985). To study (i), Poisson regression-derived rate ratios were compared according to two-month categories, ordered by baseline 25(OH)D concentrations. To study (ii), Cox regression-derived hazard ratios were compared according to quarters of baseline 25(OH)D concentrations. With respect to (i), despite a median 25(OH)D concentration ratio of 1:1.79, the trough months of 25(OH)D in March and April had a similar CVD incidence as the peak months of 25(OH)D in August and September (rate ratio: 1.07, 95\% CI: 0.98–1.17). CVD mortality was slightly higher in the trough months compared to the peak months (rate ratio: 1.27, 95\% CI: 1.12–1.44) but not compared to the other months (despite median 25[OH]D concentration ratios up to 1:1.62; p ≥ 0.077). The CVD mortality peak in January preceded the 25(OH)D trough, not adhering to the temporality criterion of Bradford Hill. With respect to (ii), compared to the lowest quarter, the highest quarter of 25(OH)D was associated with lower CVD incidence (hazard ratio: 0.82, 95\% CI: 0.76–0.89) and CVD mortality (hazard ratio: 0.64, 95\% CI: 0.57–0.72). Conclusion The present study does not support the hypothesis that seasonal increases in CVD are driven by short-term reductions in 25(OH)D. As in most observational studies, higher 25(OH)D concentrations were inversely associated with CVD.",

author = "Viktor Oskarsson and Veikko Salomaa and Pekka Jousilahti and Luigi Palmieri and Chiara Donfrancesco and Susana Sans and Licia Iacoviello and Simona Costanzo and Ferrario, \{Marco M.\} and Giancarlo Cesana and Barbara Thorand and Annette Peters and Hugh Tunstall-Pedoe and Mark Woodward and Tanja Zeller and Stefan Blankenberg and Kari Kuulasmaa and Stefan S{\"o}derberg",

note = "Publisher Copyright: {\textcopyright} 2025 Oskarsson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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Oskarsson, V, Salomaa, V, Jousilahti, P, Palmieri, L, Donfrancesco, C, Sans, S, Iacoviello, L, Costanzo, S, Ferrario, MM, Cesana, G, Thorand, B, Peters, A, Tunstall-Pedoe, H, Woodward, M, Zeller, T, Blankenberg, S, Kuulasmaa, K & Söderberg, S 2025, 'Cardiovascular disease outcomes in relation to 25-hydroxyvitamin D and its seasonal variation: Results from the BiomarCaRE consortium', PLoS ONE, vol. 20, no. 4 April, e0319607. https://doi.org/10.1371/journal.pone.0319607

TY - JOUR

T1 - Cardiovascular disease outcomes in relation to 25-hydroxyvitamin D and its seasonal variation

T2 - Results from the BiomarCaRE consortium

AU - Oskarsson, Viktor

AU - Salomaa, Veikko

AU - Jousilahti, Pekka

AU - Palmieri, Luigi

AU - Donfrancesco, Chiara

AU - Sans, Susana

AU - Iacoviello, Licia

AU - Costanzo, Simona

AU - Ferrario, Marco M.

AU - Cesana, Giancarlo

AU - Thorand, Barbara

AU - Peters, Annette

AU - Tunstall-Pedoe, Hugh

AU - Woodward, Mark

AU - Zeller, Tanja

AU - Blankenberg, Stefan

AU - Kuulasmaa, Kari

AU - Söderberg, Stefan

N1 - Publisher Copyright: © 2025 Oskarsson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2025/4/24

Y1 - 2025/4/24

N2 - Background It has been hypothesized but seldom tested that the winter excess in cardiovascular disease (CVD) is related to hypovitaminosis D. The present study examined the association between CVD and (i) seasonality of 25-hydroxyvitamin D (25[OH]D) and (ii) individual 25(OH)D concentrations. Methods and findings Harmonized 25(OH)D data were obtained from the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, including 79,570 participants examined between 1984 and 2010. One 25(OH)D measurement was available per participant. Primary endpoints were CVD incidence (coronary heart disease or stroke; n = 6006) and CVD mortality (n = 2985). To study (i), Poisson regression-derived rate ratios were compared according to two-month categories, ordered by baseline 25(OH)D concentrations. To study (ii), Cox regression-derived hazard ratios were compared according to quarters of baseline 25(OH)D concentrations. With respect to (i), despite a median 25(OH)D concentration ratio of 1:1.79, the trough months of 25(OH)D in March and April had a similar CVD incidence as the peak months of 25(OH)D in August and September (rate ratio: 1.07, 95% CI: 0.98–1.17). CVD mortality was slightly higher in the trough months compared to the peak months (rate ratio: 1.27, 95% CI: 1.12–1.44) but not compared to the other months (despite median 25[OH]D concentration ratios up to 1:1.62; p ≥ 0.077). The CVD mortality peak in January preceded the 25(OH)D trough, not adhering to the temporality criterion of Bradford Hill. With respect to (ii), compared to the lowest quarter, the highest quarter of 25(OH)D was associated with lower CVD incidence (hazard ratio: 0.82, 95% CI: 0.76–0.89) and CVD mortality (hazard ratio: 0.64, 95% CI: 0.57–0.72). Conclusion The present study does not support the hypothesis that seasonal increases in CVD are driven by short-term reductions in 25(OH)D. As in most observational studies, higher 25(OH)D concentrations were inversely associated with CVD.

AB - Background It has been hypothesized but seldom tested that the winter excess in cardiovascular disease (CVD) is related to hypovitaminosis D. The present study examined the association between CVD and (i) seasonality of 25-hydroxyvitamin D (25[OH]D) and (ii) individual 25(OH)D concentrations. Methods and findings Harmonized 25(OH)D data were obtained from the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, including 79,570 participants examined between 1984 and 2010. One 25(OH)D measurement was available per participant. Primary endpoints were CVD incidence (coronary heart disease or stroke; n = 6006) and CVD mortality (n = 2985). To study (i), Poisson regression-derived rate ratios were compared according to two-month categories, ordered by baseline 25(OH)D concentrations. To study (ii), Cox regression-derived hazard ratios were compared according to quarters of baseline 25(OH)D concentrations. With respect to (i), despite a median 25(OH)D concentration ratio of 1:1.79, the trough months of 25(OH)D in March and April had a similar CVD incidence as the peak months of 25(OH)D in August and September (rate ratio: 1.07, 95% CI: 0.98–1.17). CVD mortality was slightly higher in the trough months compared to the peak months (rate ratio: 1.27, 95% CI: 1.12–1.44) but not compared to the other months (despite median 25[OH]D concentration ratios up to 1:1.62; p ≥ 0.077). The CVD mortality peak in January preceded the 25(OH)D trough, not adhering to the temporality criterion of Bradford Hill. With respect to (ii), compared to the lowest quarter, the highest quarter of 25(OH)D was associated with lower CVD incidence (hazard ratio: 0.82, 95% CI: 0.76–0.89) and CVD mortality (hazard ratio: 0.64, 95% CI: 0.57–0.72). Conclusion The present study does not support the hypothesis that seasonal increases in CVD are driven by short-term reductions in 25(OH)D. As in most observational studies, higher 25(OH)D concentrations were inversely associated with CVD.

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Cardiovascular disease outcomes in relation to 25-hydroxyvitamin D and its seasonal variation: Results from the BiomarCaRE consortium

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