Cancer Causes & Control

, Volume 26, Issue 12, pp 1719–1728 | Cite as

Circulating 25-hydroxyvitamin D and risk of lung cancer: a dose–response meta-analysis

  • Guo-Chong Chen
  • Zeng-Li Zhang
  • Zhongxiao Wan
  • Ling Wang
  • Peter Weber
  • Manfred Eggersdorfer
  • Li-Qiang QinEmail author
  • Weiguo ZhangEmail author
Original paper



Mounting experimental evidence supports a protective effect of high 25-hydroxyvitamin D (25[OH]D), a good indicator of vitamin D status, on risk of various cancers including lung cancer. However, prospective observational studies examining the 25(OH)D–lung cancer association reported inconsistent findings. A dose–response meta-analysis was carried out to elucidate the subject.


Potentially eligible studies were identified by searching PubMed and EMBASE databases, and by carefully reviewing the bibliographies of retrieved publications. The summary relative risks (RRs) with 95 % confidence intervals (CIs) were calculated using the random-effects model.


Thirteen reports from ten prospective studies were included, totaling 2,227 lung cancer events. Results of the meta-analysis showed a significant 5 % (RR 0.95, 95 % CI 0.91–0.99) reduction in the risk of lung cancer for each 10 nmol/L increment in 25(OH)D concentrations. This inverse association was not significantly modified by area, study duration, sex, methods for 25(OH)D measurement, baseline 25(OH)D levels, or quality score of included studies. There was evidence of a nonlinear relationship between 25(OH)D and risk of lung cancer (p-nonlinearity = 0.02), with the greatest reductions in risk observed at 25(OH)D of nearly 53 nmol/L, and remained protective until approximately 90 nmol/L. Further increases showed no significant association with cancer risk, but scanty data were included in the analyses of high-level 25(OH)D. There was no evidence of publication bias.


This dose–response meta-analysis of prospective studies suggests that 25(OH)D may be associated with reduced risk of lung cancer, in particular among subjects with vitamin D deficiencies.


25-Hydroxyvitamin D Lung cancer Prospective studies Meta-analysis 


Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10552_2015_665_MOESM1_ESM.docx (30 kb)
Supplementary material 1 (DOCX 30 kb)


  1. 1.
    World Health Organization. GLOBOCAN (2012) Estimated cancer incidence, mortality and prevalence worldwide in 2012.
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefPubMedGoogle Scholar
  3. 3.
    Ezzati M, Lopez AD (2003) Estimates of global mortality attributable to smoking in 2000. Lancet 362:847–852CrossRefPubMedGoogle Scholar
  4. 4.
    Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W, Bandera EV, Gapstur S, Patel AV, Andrews K, Gansler T (2012) American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin 62:30–67CrossRefPubMedGoogle Scholar
  5. 5.
    Zerwekh JE (2008) Blood biomarkers of vitamin D status. Am J Clin Nutr 87:1087S–1091SPubMedGoogle Scholar
  6. 6.
    van der Rhee H, Coebergh JW, de Vries E (2009) Sunlight, vitamin D and the prevention of cancer: a systematic review of epidemiological studies. Eur J Cancer Prev 18:458–475CrossRefPubMedGoogle Scholar
  7. 7.
    Higashimoto Y, Ohata M, Nishio K, Iwamoto Y, Fujimoto H, Uetani K, Suruda T, Nakamura Y, Funasako M, Saijo N (1996) 1 alpha, 25-dihydroxyvitamin D3 and all-trans-retinoic acid inhibit the growth of a lung cancer cell line. Anticancer Res 16:2653–2659PubMedGoogle Scholar
  8. 8.
    Nakagawa K, Sasaki Y, Kato S, Kubodera N, Okano T (2005) 22-Oxa-1alpha,25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer. Carcinogenesis 26:1044–1054CrossRefPubMedGoogle Scholar
  9. 9.
    Hershberger PA, Modzelewski RA, Shurin ZR, Rueger RM, Trump DL, Johnson CS (1999) 1,25-Dihydroxycholecalciferol (1,25-D3) inhibits the growth of squamous cell carcinoma and down-modulates p21(Waf1/Cip1) in vitro and in vivo. Cancer Res 59:2644–2649PubMedGoogle Scholar
  10. 10.
    Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ, Mullie P, Autier P (2011) Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer 128:1414–1424CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang L, Wang S, Che X, Li X (2015) Vitamin D and lung cancer risk: a comprehensive review and meta-analysis. Cell Physiol Biochem 36:299–305CrossRefPubMedGoogle Scholar
  12. 12.
    Cheng TY, Neuhouser ML (2012) Serum 25-hydroxyvitamin D, vitamin A, and lung cancer mortality in the US population: a potential nutrient–nutrient interaction. Cancer Causes Control 23:1557–1565CrossRefPubMedGoogle Scholar
  13. 13.
    Freedman DM, Looker AC, Abnet CC, Linet MS, Graubard BI (2010) Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (1988–2006). Cancer Res 70:8587–8597PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Afzal S, Bojesen SE, Nordestgaard BG (2013) Low plasma 25-hydroxyvitamin D and risk of tobacco-related cancer. Clin Chem 59:771–780CrossRefPubMedGoogle Scholar
  15. 15.
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA 283:2008–2012CrossRefPubMedGoogle Scholar
  16. 16.
    Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P (2013) The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
  17. 17.
    Weinstein SJ, Yu K, Horst RL, Parisi D, Virtamo J, Albanes D (2011) Serum 25-hydroxyvitamin D and risk of lung cancer in male smokers: a nested case–control study. PLoS One 6:e20796PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188CrossRefPubMedGoogle Scholar
  19. 19.
    Greenland S, Longnecker MP (1992) Methods for trend estimation from summarized dose–response data, with applications to meta-analysis. Am J Epidemiol 135:1301–1309PubMedGoogle Scholar
  20. 20.
    Orsini N, Bellocco R, Greenland S (2006) Generalized least squares for trend estimation of summarized dose–respose data. Stata J 6:40–57Google Scholar
  21. 21.
    Ordonez-Mena JM, Schottker B, Fedirko V, Jenab M, Olsen A, Halkjaer J, Kampman E, de Groot L, Jansen E, Bueno-de-Mesquita HB, Peeters PH, Siganos G, Wilsgaard T, Perna L, Holleczek B, Pettersson-Kymmer U, Orfanos P, Trichopoulou A, Boffetta P, Brenner H (2015) Pre-diagnostic vitamin D concentrations and cancer risks in older individuals: an analysis of cohorts participating in the CHANCES consortium. Eur J Epidemiol. doi: 10.1007/s10654-015-0040-7
  22. 22.
    Wong YY, Hyde Z, McCaul KA, Yeap BB, Golledge J, Hankey GJ, Flicker L (2014) In older men, lower plasma 25-hydroxyvitamin D is associated with reduced incidence of prostate, but not colorectal or lung cancer. PLoS One 9:e99954PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Orsini N, Li R, Wolk A, Khudyakov P, Spiegelman D (2012) Meta-analysis for linear and nonlinear dose–response relations: examples, an evaluation of approximations, and software. Am J Epidemiol 175:66–73PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558CrossRefPubMedGoogle Scholar
  25. 25.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Freedman DM, Looker AC, Chang SC, Graubard BI (2007) Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst 99:1594–1602CrossRefPubMedGoogle Scholar
  27. 27.
    Ordonez-Mena JM, Schottker B, Haug U, Muller H, Kohrle J, Schomburg L, Holleczek B, Brenner H (2013) Serum 25-hydroxyvitamin d and cancer risk in older adults: results from a large German prospective cohort study. Cancer Epidemiol Biomark Prev 22:905–916CrossRefGoogle Scholar
  28. 28.
    Ananthakrishnan AN, Cheng SC, Cai T, Cagan A, Gainer VS, Szolovits P, Shaw SY, Churchill S, Karlson EW, Murphy SN, Kohane I, Liao KP (2014) Association between reduced plasma 25-hydroxy vitamin D and increased risk of cancer in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 12:821–827PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, Willett WC (2006) Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 98:451–459CrossRefPubMedGoogle Scholar
  30. 30.
    Kilkkinen A, Knekt P, Heliovaara M, Rissanen H, Marniemi J, Hakulinen T, Aromaa A (2008) Vitamin D status and the risk of lung cancer: a cohort study in Finland. Cancer Epidemiol Biomark Prev 17:3274–3278CrossRefGoogle Scholar
  31. 31.
    Skaaby T, Husemoen LL, Thuesen BH, Pisinger C, Jorgensen T, Roswall N, Larsen SC, Linneberg A (2014) Prospective population-based study of the association between serum 25-hydroxyvitamin-D levels and the incidence of specific types of cancer. Cancer Epidemiol Biomark Prev 23:1220–1229CrossRefGoogle Scholar
  32. 32.
    Chien KL, Hsu HC, Chen PC, Lin HJ, Su TC, Chen MF, Lee YT (2015) Total 25-hydroxyvitamin D concentration as a predictor for all-cause death and cardiovascular event risk among ethnic Chinese adults: a cohort study in a Taiwan community. PLoS One 10:e0123097PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Durup D, Jorgensen HL, Christensen J, Schwarz P, Heegaard AM, Lind B (2012) A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study. J Clin Endocrinol Metab 97:2644–2652CrossRefPubMedGoogle Scholar
  34. 34.
    Ford ES, Zhao G, Tsai J, Li C (2011) Vitamin D and all-cause mortality among adults in USA: findings from the National Health and Nutrition Examination Survey Linked Mortality Study. Int J Epidemiol 40:998–1005CrossRefPubMedGoogle Scholar
  35. 35.
    Grant WB (2010) Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B 101:130–136CrossRefPubMedGoogle Scholar
  36. 36.
    Kristal AR, Till C, Song X, Tangen CM, Goodman PJ, Neuhauser ML, Schenk JM, Thompson IM, Meyskens FL Jr, Goodman GE, Minasian LM, Parnes HL, Klein EA (2014) Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol Biomark Prev 23:1494–1504CrossRefGoogle Scholar
  37. 37.
    Brandenburg VM, Vervloet MG, Marx N (2012) The role of vitamin D in cardiovascular disease: from present evidence to future perspectives. Atherosclerosis 225:253–263CrossRefPubMedGoogle Scholar
  38. 38.
    Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA (2011) The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 96:53–58PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW (2008) Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 181:7090–7099PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Ordonez-Moran P, Larriba MJ, Pendas-Franco N, Aguilera O, Gonzalez-Sancho JM, Munoz A (2005) Vitamin D and cancer: an update of in vitro and in vivo data. Front Biosci 10:2723–2749CrossRefPubMedGoogle Scholar
  41. 41.
    Afzal S, Bojesen SE, Nordestgaard BG (2013) Low 25-hydroxyvitamin D and risk of type 2 diabetes: a prospective cohort study and meta-analysis. Clin Chem 59:381–391CrossRefPubMedGoogle Scholar
  42. 42.
    Lee JY, Jeon I, Lee JM, Yoon JM, Park SM (2013) Diabetes mellitus as an independent risk factor for lung cancer: a meta-analysis of observational studies. Eur J Cancer 49:2411–2423CrossRefPubMedGoogle Scholar
  43. 43.
    Cheng TY, Goodman GE, Thornquist MD, Barnett MJ, Beresford SA, LaCroix AZ, Zheng Y, Neuhouser ML (2014) Estimated intake of vitamin D and its interaction with vitamin A on lung cancer risk among smokers. Int J Cancer 135:2135–2145PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Cheng TY, Lacroix AZ, Beresford SA, Goodman GE, Thornquist MD, Zheng Y, Chlebowski RT, Ho GY, Neuhouser ML (2013) Vitamin D intake and lung cancer risk in the Women’s Health Initiative. Am J Clin Nutr 98:1002–1011PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Redaniel MT, Gardner MP, Martin RM, Jeffreys M (2014) The association of vitamin D supplementation with the risk of cancer in postmenopausal women. Cancer Causes Control 25:267–271CrossRefPubMedGoogle Scholar
  46. 46.
    Takata Y, Shu XO, Yang G, Li H, Dai Q, Gao J, Cai Q, Gao YT, Zheng W (2013) Calcium intake and lung cancer risk among female nonsmokers: a report from the Shanghai Women’s Health Study. Cancer Epidemiol Biomark Prev 22:50–57CrossRefGoogle Scholar
  47. 47.
    Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ (2003) Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77:204–210PubMedGoogle Scholar
  48. 48.
    Lazzeroni M, Serrano D, Pilz S, Gandini S (2013) Vitamin D supplementation and cancer: review of randomized controlled trials. Anticancer Agents Med Chem 13:118–125CrossRefPubMedGoogle Scholar
  49. 49.
    Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA (2011) Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med 155:827–838CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Guo-Chong Chen
    • 1
  • Zeng-Li Zhang
    • 2
  • Zhongxiao Wan
    • 1
  • Ling Wang
    • 3
  • Peter Weber
    • 4
  • Manfred Eggersdorfer
    • 4
  • Li-Qiang Qin
    • 1
    Email author
  • Weiguo Zhang
    • 5
    Email author
  1. 1.Department of Nutrition and Food Hygiene, School of Public HealthSoochow UniversitySuzhouChina
  2. 2.Department of Labor Hygiene and Environmental Health, School of Public HealthSoochow UniversitySuzhouChina
  3. 3.Special Procurement WardThe First Affiliated Hospital of Soochow UniversitySuzhouChina
  4. 4.DSM Nutritional Products Ltd., Human Nutrition and HealthKaiseraugstSwitzerland
  5. 5.DSM Nutritional Products Ltd., Human Nutrition and HealthBeijingChina

Personalised recommendations