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Circulating 25-hydroxyvitamin D levels and hypertension risk after adjusting for publication bias

Abstract

Background

Previous systematic reviews reported that serum vitamin D deficiency was associated with risk of hypertension. The aim was to conduct a meta-epidemiological analysis for evaluating the potential effects of publication bias.

Methods

The selection criterion was defined as a follow-up study for evaluating the association between circulating 25-hydroxyvitam D level and hypertension risk in adults. A funnel plot and Egger’s test were used to detect a publication bias. If a publication bias was identified, trim-and-fill analysis (TFA) with linear estimator was performed to estimate a summary relative risk (sRR).

Results

The meta-analysis of 13 cohorts resulted in the lower the vitamin D, the higher the risk of hypertension statistically significant (sRR, 1.22; 95% confidence interval [CI], 1.05 to 1.41). But The P-value of Egger’s test (=0.015) and asymmetry of the funnel plot showed that there was a publication bias. TFA resulted in that statistical significance disappeared in the association between vitamin D level and hypertension risk in total cohorts (filled sRR, 1.03; 95% CI, 0.89 to 1.18) as well as men and women cohorts.

Conclusions

The publication bias-adjusted results by TFA had no statistically significant association between vitamin D levels and the risk of hypertension. The significant results in previous systematic reviews might be interpreted as due to publication bias.

Background

Vitamin D is associated with the renin-angiotensin system, vascular inflammation, and calcification [1,2,3,4]. Based on these facts, the hypothesis that circulating vitamin D level would be associated with a risk of hypertension has been consistently suggested [5].

Four systematic reviews evaluating the hypothesis were published [6,7,8,9]. They all concluded that there was a statistical significance between lower level of circulating 25 hydroxyvitamin D [25(OH)D] and risk of hypertension (Table 1). However, as shown in Table 1, the existing systematic reviews did not sufficiently consider the publication bias through funnel plot and Egger’s test.

Table 1 Summary of previous systematic reviews for evaluating the association between serum 25(OH) vitamin D levels and hypertension risk

Meanwhile, vitamin D deficiency is more common in women [10]. Therefore, the risk of hypertension due to vitamin D deficiency can be expected to vary by sex. But the existing systematic reviews in Table 1 did not present the summary relative risk (sRR) of subgroup analysis by sex. The aim was to conduct a meta-epidemiological analysis [11] for evaluating the association between serum 25(OH)D levels and hypertension risk in men and women after adjusting publication bias.

Methods

Selection strategies

A total of 11 studies selected for meta-analysis by four systematic reviews in Table 1 were selected as potential study subjects [9, 12,13,14,15,16,17,18,19,20,21]. Considering that the most recently published year among these was 2017 [9], it was necessary to secure additional articles to be selected as of November 30, 2020. Accordingly, a list of articles that cited previously selected 11 papers was made using the ‘cited by’ option provided by PubMed [22].

Then, each article was evaluated whether it satisfies the selection criterion such as a follow-up study for evaluating the association between circulating 25(OH)D level and hypertension risk in adults. After selecting the articles that satisfy the selection criterion, it was checked whether the participants duplicate among the selected studies. If there were overlaps in the study participants, a study with a larger number of hypertensive patients was selected.

Statistical analysis

The sRR adjusted for the most confounders in each study were extracted. The lowest to highest sRR values were unified to determine the risk of hypertension due to vitamin D deficiency. If the sRR was presented with the lowest circulating 25(OH)D level as the reference, the inverse was used such that the highest level as the reference.

Heterogeneity of studies was assessed with I-squared value (%). Random effects model meta-analysis was performed [23]. Publication bias was examined by funnel plot and Egger’s test [24, 25]. If a publication bias was identified, trim-and-fill analysis (TFA) with linear estimator was performed using fixed-random effects model in STATA ver. 14.2 (StataCorp, TX, USA) [26, 27]. The statistical significance level was set to 0.05. The author followed the guideline for reporting meta-epidemiological methodology research [11].

Results

Final selection

Among 11 articles selected by 4 systematic reviews in Table 1, Griffine et al. [16] was excluded because the follow-up outcome was not hypertension but systolic blood pressure. And a total of 621 studies cited the 11 studies, and 3 studies were also secured [28,29,30]. And Qi et al. [9] and Peng et al. [28] had the same participants, so Peng et al. [28] was excluded because it had fewer hypertension patients. Finally, 12 studies having 13 cohorts were selected [9, 12,13,14,15,16,17,18,19,20,21, 29, 30] (Fig. 1). When organized by sex, it is classified into 3 men, 3 women, and 7 sex-adjusted cohorts.

Fig. 1
figure 1

Flow chart of the final selection of follow-up studies

Summary effect size

The meta-analysis of 13 cohorts resulted in the lower the vitamin D, the higher the risk of hypertension statistically significant (sRR, 1.22; 95% confidence interval [CI], 1.05 to 1.41; I-squared, 77.2%) (Fig. 2). The P-value of Egger’s test (=0.015) and asymmetry of funnel plot (Fig. 3) showed that there was a publication bias. And TFA resulted in that statistical significance disappeared in the association between vitamin D level and hypertension risk (filled sRR, 1.03; 95% CI. 0.89 to 1.18) (Table 2).

Fig. 2
figure 2

Forest plot (CI: confidence interval; ES: effect size)

Fig. 3
figure 3

Funnel plot (P-value of Egger’s test =0.015; logrr: logarithm of relative risk; s.e.: standard error)

Table 2 Subgroup analysis by potential confoundersa

Subgroup analysis

In the subgroup analysis by 3 sex group, only women cohorts had statistical significance (sRR, 1.50; 95%CI. 1.03 to 2.19; I-squared, 43.4%) (Fig. 2). However, TFA in women cohorts resulted in that statistical significance disappeared (filled sRR, 1.16; 95% CI, 0.77 to 1.75) (Table 2).

Discussion

Comparison of results of previous systematic reviews

The main result was that a lower level of circulating 25(OH)D was associated with a significant, 1.22-fold (95% CI, 1.05 to 1.41) increase in hypertension risk in adults while publication bias exists. The above results obtained from 12 studies were like the results of Qi et al. [9] estimated from 7 studies (sRR = 1.24, 95%CI: 1.08–1.41). The I-squared value representing the level of heterogeneity was also similar (77.2% vs 72.1%).

However, the TFA considering publication bias resulted in that there was no association between vitamin D level and hypertension risk regardless of sex groups (Table 2). These results were like Zhang et al. [31]. They performed dose-response meta-analyses by sex. While the P-value of Egger’s test was 0.38, the hypertension risk per 25 nmol/L increments in 25(OH)D levels did not have statistical significance in men (95% CI, 0.85 to 1.00) and in women (95% CI, 0.76 to 1.01).

Adjustment of publication bias

The funnel plot to check a publication bias showed asymmetry in this study. Only Kunutsor et al. [8] in Table 1 mentioned the funnel plot in Method. While they selected 6 studies for meta-analysis, they did not draw the plot based on that it was not useful in meta-analysis selecting less than five studies. Instead, they judged no evidence of publication bias by P-value of Egger’s test (=0.08). Thus, there is necessary to adjust the positivity criterion of presenting a publication bias in Egger’s test as P-value < 0.1 [32]. In addition, the P-value of Egger’s test in Burgaz et al. [7] containing 3 studies was 0.36. These facts illustrated that the P-value of Egger’s test decreased as the increased number of selected studies for meta-analysis.

In addition to publication bias, causes of funnel plot asymmetry involve chance, choice of effect measure, choice of precision measurement, and heterogeneity [33]. The selected cohorts were 12 studies, so that chance could be ruled out. And effect measures and precision measures could be rule out because the selected studies have the same study design.

Strengths and Limitations

The major strength of this study was secured two additional studies [29, 30] so that the number of selected studies for meta-analysis could be over 10. This is one of four criteria for appropriateness of statistical tests for publication bias suggested by Ioannidis and Trikalinos [34]. Accordingly, it was possible to confirm publication bias by Egger’s test, and to provide bias-adjusted results by TFA [35]. In contrast, previous systematic reviews in Table 1 could not sufficiently consider publication bias and did not perform TFA.

The main limitation was related to the limitations of TFA. The effect size adjusted for publication bias provided by TFA should meet with the assumption that asymmetry in the funnel plot was only caused by publication bias [36]. Because this study could not rule out the asymmetry of funnel plot was made by heterogeneity [27]. But the bias-adjusted results by TFA having no statistically significant association between vitamin D levels and the risk of hypertension might be valid based on that publication bias is commonly associated with the inflated intervention effect [35]. In addition, TFA should be performed with great caution when using software programs [27]. Because there were 3 types of the estimator determining the number of points to trim in each iteration [27]. Author selected the linear estimator because it is stable in most situations and is the default in STATA software [26]. Another limitation was that different studies have different criteria for categorizing serum 25(OH)D levels. Therefore, the author performed a meta-analysis by extracting the outcomes of the lowest to the highest level.

Conclusion

In conclusion, the bias-adjusted results by TFA had no statistically significant association between vitamin D levels and the risk of hypertension. The significant results in previous systematic reviews could be interpreted as due to publication bias.

Availability of data and materials

No data.

Abbreviations

25(OD)D:

25-hydroxyvitamin D

CI:

Confidence intervals

sRR:

Summary relative risk

TFA:

Trim-and-fill analysis

References

  1. Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5:819–29.

    CAS  Article  Google Scholar 

  2. Pilz S, Verheyen N, Grübler MR, Tomaschitz A, März W. Vitamin D and cardiovascular disease prevention. Nat Rev Cardiol. 2016;13:404–17.

    CAS  Article  Google Scholar 

  3. Al Mheid I, Quyyumi AA. Vitamin D and cardiovascular disease: controversy unresolved. J Am Coll Cardiol. 2017;70:89–100.

    Article  Google Scholar 

  4. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–81.

    CAS  Article  Google Scholar 

  5. Jeong HY, Park KM, Lee MJ, Yang DH, Kim SH, Lee SY. Vitamin D and hypertension. Electrolyte Blood Press. 2017;15:1–11.

    CAS  Article  Google Scholar 

  6. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K. Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med. 2010;152:307–14.

    Article  Google Scholar 

  7. Burgaz A, Orsini N, Larsson SC, Wolk A. Blood 25-hydroxyvitamin D concentration and hypertension: a meta-analysis. J Hypertens. 2011;29:636–45.

    CAS  Article  Google Scholar 

  8. Kunutsor SK, Apekey TA, Steur M. Vitamin D and risk of future hypertension: meta-analysis of 283,537 participants. Eur J Epidemiol. 2013;28:205–21.

    CAS  Article  Google Scholar 

  9. Qi D, Nie XL, Wu S, Cai J. Vitamin D and hypertension: prospective study and meta-analysis. PLoS One. 2017;12:e0174298.

    Article  Google Scholar 

  10. Chen CH, Liu LK, Chen MJ, Lee WJ, Lin MH, Peng LN. Associations between vitamin D deficiency, musculoskeletal health, and cardiometabolic risk among community-living people in Taiwan: Age and sex-specific relationship. Medicine (Baltimore). 2018;97:e13886.

    CAS  Article  Google Scholar 

  11. Murad MH, Wang Z. Guidelines for reporting meta-epidemiological methodology research. Evid Based Med. 2017;22:139–42.

    Article  Google Scholar 

  12. Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension. 2007;49:1063–9.

    CAS  Article  Google Scholar 

  13. Forman JP, Curhan GC, Taylor EN. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension among young women. Hypertension. 2008;52:828–32.

    CAS  Article  Google Scholar 

  14. Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, et al. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. 2010;106:963–8.

    CAS  Article  Google Scholar 

  15. Jorde R, Figenschau Y, Emaus N, Hutchinson M, Grimnes G. Serum 25-hydroxyvitamin D levels are strongly related to systolic blood pressure but do not predict future hypertension. Hypertension. 2010;55:792–8.

    CAS  Article  Google Scholar 

  16. Griffin FC, Gadegbeku CA, Sowers MR. Vitamin D and subsequent systolic hypertension among women. Am J Hypertens. 2011;24:316–21.

    CAS  Article  Google Scholar 

  17. Margolis KL, Martin LW, Ray RM, Kerby TJ, Allison MA, Curb JD, et al. A prospective study of serum 25-hydroxyvitamin D levels, blood pressure, and incident hypertension in postmenopausal women. Am J Epidemiol. 2012;175:22–32.

    Article  Google Scholar 

  18. Skaaby T, Husemoen LL, Pisinger C, Jørgensen T, Thuesen BH, Fenger M, et al. Vitamin D status and changes in cardiovascular risk factors: a prospective study of a general population. Cardiology. 2012;123:62–70.

    CAS  Article  Google Scholar 

  19. Wang L, Ma J, Manson JE, Buring JE, Gaziano JM, Sesso HD. A prospective study of plasma vitamin D metabolites, vitamin D receptor gene polymorphisms, and risk of hypertension in men. Eur J Nutr. 2013;52:1771–9.

    CAS  Article  Google Scholar 

  20. van Ballegooijen AJ, Kestenbaum B, Sachs MC, de Boer IH, Siscovick DS, Hoofnagle AN, et al. Association of 25-hydroxyvitamin D and parathyroid hormone with incident hypertension: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2014;63:1214–22.

    Article  Google Scholar 

  21. Ke L, Graubard BI, Albanes D, Fraser DR, Weinstein SJ, Virtamo J, et al. Hypertension, pulse, and other cardiovascular risk factors and vitamin D status in Finnish men. Am J Hypertens. 2013;26:951–6.

    CAS  Article  Google Scholar 

  22. Bae JM, Kim EH. Citation discovery tools for conducting adaptive meta-analyses to update systematic reviews. J Prev Med Public Health. 2016;49:129–33.

    Article  Google Scholar 

  23. Harris RJ, Bradburn MJ, Deeks JJ, Harbord RM, Altman DG, Sterne JAC. metan: Fixed- and random-effects meta-analysis. Stata J. 2008;8:3–28.

    Article  Google Scholar 

  24. Song F, Parekh S, Hooper L, Loke YK, Ryder J, Sutton AJ, et al. Dissemination and publication of research findings: an updated review of related biases. Health Technol Assess. 2010;14:1–193.

    Article  Google Scholar 

  25. Moreno SG, Sutton AJ, Ades AE, Stanley TD, Abrams KR, Peters JL, et al. Assessment of regression-based methods to adjust for publication bias through a comprehensive simulation study. BMC Med Res Methodol. 2009;9:2.

    Article  Google Scholar 

  26. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56:455–63.

    CAS  Article  Google Scholar 

  27. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Performance of the trim and fill method in the presence of publication bias and between-study heterogeneity. Stat Med. 2007;26:4544–62.

    Article  Google Scholar 

  28. Peng M, Chen S, Jiang X, Zhang W, Wang Y, Wu S, et al. Dissociation between low vitamin D level and hypertension in coal mine workers: evidence from the Kailuan study. Intern Med. 2016;55:1255–60.

    CAS  Article  Google Scholar 

  29. Mirhosseini N, Vatanparast H, Kimball SM. The association between serum 25(OH)D status and blood pressure in participants of a community-based program taking vitamin D supplements. Nutrients. 2017;9:1244.

    Article  Google Scholar 

  30. van Ballegooijen AJ, Gansevoort RT, Lambers-Heerspink HJ, de Zeeuw D, Visser M, Brouwer IA, et al. Plasma 1,25-dihydroxyvitamin D and the risk of developing hypertension: the prevention of renal and vascular end-stage disease study. Hypertension. 2015;66:563–70.

    Article  Google Scholar 

  31. Zhang D, Cheng C, Wang Y, Wang Y, Sun H, Yu S, et al. Effect of vitamin D on blood pressure and hypertension in the general population: an update meta-analysis of cohort studies and randomized controlled trials. Prev Chronic Dis. 2020;17:E03.

    Article  Google Scholar 

  32. Hayashino Y, Noguchi Y, Fukui T. Systematic evaluation and comparison of statistical tests for publication bias. J Epidemiol. 2005;15:235–43.

    Article  Google Scholar 

  33. Terrin N, Schmid C, Lau J. In an empirical evaluation of the funnel plot, researchers cound not visually identify publication bias. J Clin Epidemiol. 2005;58:894–901.

    Article  Google Scholar 

  34. Ioannidis JP, Trikalinos TA. The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. CMAJ. 2007;176:1091–6.

    Article  Google Scholar 

  35. Murad MH, Chu H, Lin L, Wang Z. The effect of publication bias magnitude and direction on the certainty in evidence. BMJ Evid Based Med. 2018;23:84–6.

    Article  Google Scholar 

  36. Mavridis D, Salanti G. Exploring and accounting for publication bias in mental health: a brief overview of methods. Evid Based Ment Health. 2014;17:11–5.

    Article  Google Scholar 

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Acknowledgements

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Funding

This work was supported by the 2021 education, research, and student guidance grant funded by Jeju National University, Korea.

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JMB contributed the conception and design of the study, conduction of searching process, statistical analysis, and interpretation of results, and draft the manuscript. The author(s) read and approved the final manuscript.

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Correspondence to Jong-Myon Bae.

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Bae, JM. Circulating 25-hydroxyvitamin D levels and hypertension risk after adjusting for publication bias. Clin Hypertens 28, 15 (2022). https://doi.org/10.1186/s40885-022-00196-4

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Keywords

  • Vitamin D
  • Hypertension
  • Publication bias
  • Systematic review
  • Meta-analysis