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Genomics and personalized strategies in nutrition

Variability in response to vitamin D supplementation according to vitamin D metabolism related gene polymorphisms in healthy adults

European Journal of Clinical Nutrition volume 77, pages 189–194 (2023)Cite this article

Subjects

Abstract

Objective

The aim of this study was to determine the influence of polymorphisms in some key gene actors of the vitamin D (vitD) metabolic pathway on supplementation efficacy.

Methods

In total, 245 healthy participants were recruited from occupational medicine service in Sahloul University Hospital with vitD deficiency [25(OH)D ≤ 30 ng/ml]. After giving an informed consent, all participants were asked to complete a generalized questionnaire and to follow a detailed personalized supplementation protocol. Genetic study was performed by PCR-RFLP for 15 single nucleotide polymorphisms (SNPs) belonging to DBP, CYP2R1, CYP27B14, CYP24A1 and VDR genes. Statistical study was carried out with SPSS23.0.

Results

Among the studied SNPs, non-response was significantly associated with variant alleles of rs4588 (OR* = 11.51; p < 0.001), rs10766197 (OR* = 6.92; p = 0.008) and rs12794714 (OR* = 5.09; p = 0.004). These three SNPs contributed in 18.8% in response variability with rs4588 being the most influential (10.3%). There was a significant linear negative correlation between baseline 25(OH)D and post supplementation 25(OH)D concentration (r = −0.437; p < 0.001) as well as a linear negative association between the increase in 25(OH)D concentration and GRS (GRS: genetic risk score = the sum of risk alleles) (r = −0.149; p = 0.033).

Conclusions

DBP-rs4588, CYP2R1-rs10766197 and rs12794714 variants are associated with variations in serum 25(OH)D concentrations and efficacy of response to vitD supplementation in Tunisian adults. Taking into account these variations can help to better adapt vitD intake to ensure a higher response to supplementation.

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Fig. 1: Comparison between vitamin D concentrations at baseline and after supplementation according to GRS category.
Fig. 2: Correlation between 25(OH)D increase and baseline concentration.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Zhang Y, Fang F, Tang J, Jia L, Feng Y, Xu P, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ. 2019;366:l4673.

    Article  Google Scholar 

  2. Stokes CS, Lammert F. Vitamin D supplementation: less controversy, more guidance needed. F1000Research. 2016;4–5.

  3. Amrein K, Scherkl M, Hoffmann M, Neuwersch-Sommeregger S, Köstenberger M, Tmava Berisha A, et al. Vitamin D deficiency 2.0: an update on the current status worldwide. Eur. J. Clin. Nutr. 2020;74:1498–513.

    Article  CAS  Google Scholar 

  4. Bouillon R, Lips P, Bilezikian JP. Vitamin D supplementation and musculoskeletal health. Lancet Diabetes Endocrinol. 2019;7:85–6.

    Article  Google Scholar 

  5. Dawson-Hughes B, Staten MA, Knowler WC, Nelson J, Vickery EM, LeBlanc ES, et al. Intratrial exposure to vitamin D and new-onset diabetes among adults with prediabetes: a secondary analysis from the vitamin D and type 2 diabetes (D2d) study. Diabetes Care. 2020;43:2916–22.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Wimalawansa S. Causes, benefits and consequences of vitamin D deficiency. 2019.

  8. Meddeb N, Sahli H, Chahed M, Abdelmoula J, Feki M, Salah H, et al. Vitamin D deficiency in Tunisia. Osteoporos Int. 2005;16:180–3.

    Article  CAS  Google Scholar 

  9. Mazahery H, Von, Hurst PR. Factors affecting 25-hydroxyvitamin D concentration in response to vitamin D supplementation. Nutrients. 2015;7:5111–42.

    Article  CAS  Google Scholar 

  10. Jiang X, Kiel DP, Kraft P. The genetics of vitamin D. Bone. 2019;126:59–77.

    Article  CAS  Google Scholar 

  11. Waterhouse M, Tran B, Armstrong BK, Baxter C, Ebeling PR, English DR, et al. Environmental, personal, and genetic determinants of response to vitamin D supplementation in older adults. J Clin Endocrinol Metab. 2014;99:E1332–40.

    Article  CAS  Google Scholar 

  12. Yao P, Sun L, Lu L, Ding H, Chen X, Tang L, et al. Effects of genetic and nongenetic factors on total and bioavailable 25 (OH) D responses to vitamin D supplementation. J Clin Endocrinol Metab. 2017;102:100–10.

    Article  Google Scholar 

  13. Rouillon V, Dubourg G, Gauvain J-B, Baron D, Glemarec J, Cormier G, et al. Insuffisance en vitamine D: évaluation d’une supplémentation orale standardisée utilisant des ampoules de 100 000 IU de cholécalciferol, en fonction du taux sérique initial de 25OH vitamine D. Rev du Rhum. 2012;79:351–4.

    Article  Google Scholar 

  14. Pott-Junior H, Luzeiro C, Senise JF, Castelo A. Association of seasonality and serum albumin concentration with vitamin D deficiency in subjects with chronic hepatitis C infection living in a sunny country. Public Health Nutr. 2020;23:1247–53.

    Article  Google Scholar 

  15. Al-Daghri NM, Mohammed AK, Bukhari I, Rikli M, Abdi S, Ansari MGA, et al. Efficacy of vitamin D supplementation according to vitamin D-binding protein polymorphisms. Nutrition. 2019;63:148–54.

    Article  Google Scholar 

  16. Nissen J, Vogel U, Ravn-Haren G, Andersen EW, Madsen KH, Nexø BA, et al. Common variants in CYP2R1 and GC genes are both determinants of serum 25-hydroxyvitamin D concentrations after UVB irradiation and after consumption of vitamin D3–fortified bread and milk during winter in Denmark. Am J Clin Nutr. 2015;101:218–27.

    Article  CAS  Google Scholar 

  17. Nimitphong H, Saetung S, Chanprasertyotin S, Chailurkit L-O, Ongphiphadhanakul B. Changes in circulating 25-hydroxyvitamin D according to vitamin D binding protein genotypes after vitamin D 3 or D 2 supplementation. Nutr J. 2013;12:39.

    Article  CAS  Google Scholar 

  18. Pooyan S, Rahimi MH, Mollahosseini M, Khorrami-Nezhad L, Maghbooli Z, Mirzaei K. The Association between Vitamin D Deficiency and variants of Vitamin D Binding protein gene among Healthy Iranian Adults. Int. J. Vitam. Nutr. Res. 2019;90:249–56.

    Article  Google Scholar 

  19. Mehramiz M, Khayyatzadeh SS, Esmaily H, Ghasemi F, Sadeghi-Ardekani K, Tayefi M, et al. Associations of vitamin D binding protein variants with the vitamin D-induced increase in serum 25-hydroxyvitamin D. Clin Nutr ESPEN. 2019;29:59–64.

    Article  Google Scholar 

  20. Slow S, Pearson JP, Florkowski CM, Elder PA, Lewis JG, Kennedy MA, et al. Effect of genetic factors on the response to vitamin D3 supplementation in the VIDARIS randomized controlled trial. Nutrition. 2020;75:110761.

    Article  Google Scholar 

  21. Xu X, Mao J, Zhang M, Liu H, Li H, Lei H, et al. Vitamin D deficiency in Uygurs and Kazaks is associated with polymorphisms in CYP2R1 and DHCR7/NADSYN1 genes. Med Sci Monit Int Med J Exp Clin Res. 2015;21:1960.

    CAS  Google Scholar 

  22. Bahrami A, Mehramiz M, Ghayour-Mobarhan M, Bahrami-Taghanaki H, Ardekani KS, Tayefi M, et al. A genetic variant in the cytochrome P450 family 2 subfamily R member 1 determines response to vitamin D supplementation. Clin Nutr. 2019;38:676–81.

    Article  CAS  Google Scholar 

  23. Barry EL, Rees JR, Peacock JL, Mott LA, Amos CI, Bostick RM, et al. Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial. J Clin Endocrinol Metab. 2014;99:E2133–7.

    Article  CAS  Google Scholar 

  24. Tomei S, Singh P, Mathew R, Mattei V, Garand M, Alwakeel M, et al. The role of polymorphisms in vitamin D-related genes in response to vitamin D supplementation. Nutrients. 2020;12:2608.

    Article  CAS  Google Scholar 

  25. Shinkyo R, Sakaki T, Kamakura M, Ohta M, Inouye K. Metabolism of vitamin D by human microsomal CYP2R1. Biochem Biophys Res Commun. 2004;324:451–7.

    Article  CAS  Google Scholar 

  26. Yu F, Wang C, Wang L, Jiang H, Ba Y, Cui L, et al. Study and evaluation the impact of vitamin D receptor variants on the risk of type 2 diabetes mellitus in Han Chinese: 中国汉族人群中维生素 D 受体基因多态性与 2 型糖尿病的关系分析和评价. J Diabetes. 2017;9:275–84.

    Article  CAS  Google Scholar 

  27. Williams CE, Williams EA, Corfe BM. Rate of change of circulating 25-hydroxyvitamin D following sublingual and capsular vitamin D preparations. Eur J Clin Nutr. 2019;73:1630–5.

    Article  CAS  Google Scholar 

  28. Sluyter JD, Camargo CA Jr, Stewart AW, Waayer D, Lawes CM, Toop L, et al. Effect of monthly, high‐dose, long‐term vitamin D supplementation on central blood pressure parameters: a randomized controlled trial substudy. J Am Heart Assoc. 2017;6:e006802.

    Article  Google Scholar 

  29. Sluyter JD, Camargo CA, Waayer D, Lawes CM, Toop L, Khaw K-T, et al. Effect of monthly, high-dose, long-term vitamin D on lung function: a randomized controlled trial. Nutrients. 2017;9:1353.

    Article  Google Scholar 

  30. Arabi A, Khoueiry-Zgheib N, Awada Z, Mahfouz R, Al-Shaar L, Hoteit M, et al. CYP2R1 polymorphisms are important modulators of circulating 25-hydroxyvitamin D levels in elderly females with vitamin insufficiency, but not of the response to vitamin D supplementation. Osteoporos Int. 2017;28:279–90.

    Article  CAS  Google Scholar 

  31. Chun RF. New perspectives on the vitamin D binding protein. Cell Biochem Funct. 2012;30:445–56.

    Article  CAS  Google Scholar 

  32. de Oliveira LF, de Azevedo LG, da Mota Santana J, de Sales LPC, Pereira-Santos M. Obesity and overweight decreases the effect of vitamin D supplementation in adults: systematic review and meta-analysis of randomized controlled trials. Rev. Endocr. Metab. Disord.2020;21:67–76.

    Article  CAS  Google Scholar 

  33. Zittermann A, Ernst JB, Gummert JF, Börgermann J. Vitamin D supplementation, body weight and human serum 25-hydroxyvitamin D response: a systematic review. Eur J Nutr. 2014;53:367–74.

    Article  CAS  Google Scholar 

  34. Ekwaru JP, Zwicker JD, Holick MF, Giovannucci E, Veugelers PJ. The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers. PLoS ONE. 2014;9:e111265.

    Article  Google Scholar 

  35. Griffin G, Hewison M, Hopkin J, Kenny RA, Quinton R, Rhodes J, et al. Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19. Clin Med. 2021;21:e144.

    Article  Google Scholar 

  36. Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, et al. Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions. Endocr Rev. 2019;40:1109–51.

    Article  Google Scholar 

  37. Ketha H, Thacher TD, Oberhelman SS, Fischer PR, Singh RJ, Kumar R. Comparison of the effect of daily versus bolus dose maternal vitamin D3 supplementation on the 24, 25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 ratio. Bone. 2018;110:321–5.

    Article  CAS  Google Scholar 

  38. Jääskeläinen T, Itkonen ST, Lundqvist A, Erkkola M, Koskela T, Lakkala K, et al. The positive impact of general vitamin D food fortification policy on vitamin D status in a representative adult Finnish population: evidence from an 11-y follow-up based on standardized 25-hydroxyvitamin D data. Am J Clin Nutr. 2017;105:1512–20.

    Google Scholar 

  39. Pludowski P, Holick MF, Grant WB, Konstantynowicz J, Mascarenhas MR, Haq A, et al. Vitamin D supplementation guidelines. J Steroid Biochem Mol Biol. 2018;175:125–35.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the Tunisian Ministry of Higher Education, Scientific Research and Technology and the Ministry of Health for their support. The authors are thankful to all the members of the biochemistry laboratory of Sahloul University Hospital for their cooperation in conducting this research specially Mrs. Henda Falfoul and Mr. Mahmoud Smida. Finally, we gratefully acknowledge the contribution of participating individuals whose cooperation made this study possible.

Funding

This study was funded by grants from the Tunisian Ministry of Higher Education, Scientific Research and Technology and the Ministry of Health.

Author information

Authors and Affiliations

  1. Biochemistry Department, LR12SP11, Sahloul University Hospital, Sousse, Tunisia

    Mariem Ammar, Syrine Heni, Mohamed Sahbi Tira, Yassine Khalij, Haithem Hamdouni, Dorra Amor, Asma Omezzine & Ali Bouslama

  2. University of Monastir Faculty of Pharmacy, Monastir, Tunisia

    Mariem Ammar, Syrine Heni, Mohamed Sahbi Tira, Yassine Khalij, Haithem Hamdouni, Dorra Amor, Asma Omezzine & Ali Bouslama

  3. Occupational Health Service, Sahloul University Hospital, Sousse, Tunisia

    Sonia Ksibi

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Contributions

This study was supervised by AO and AB. MA, YK and HH designed the study and were responsible for screening potentially eligible studies. MA, SH and MST recruited the patients under the supervision of SK. MA performed the genotyping. AO and MA performed the statistical analysis and the interpretation of the data. MA wrote the manuscript. AO and DA provided a critical review of the manuscript.

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Correspondence to Mariem Ammar.

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Ammar, M., Heni, S., Tira, M.S. et al. Variability in response to vitamin D supplementation according to vitamin D metabolism related gene polymorphisms in healthy adults. Eur J Clin Nutr 77, 189–194 (2023). https://doi.org/10.1038/s41430-022-01218-y

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