Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Integrative Biology

Genetic association analysis of vitamin D pathway with obesity traits

International Journal of Obesity volume 37, pages 1399–1406 (2013)Cite this article

Subjects

Abstract

Objective:

Observational studies have examined the link between vitamin D deficiency and obesity traits. Some studies have reported associations between vitamin D pathway genes such as VDR, GC and CYP27B1 with body mass index (BMI) and waist circumference (WC); however, the findings have been inconsistent. Therefore, we investigated the involvement of vitamin D metabolic pathway genes in obesity-related traits in a large population-based study.

Methods:

We undertook a comprehensive analysis between 100 tagging single nucleotide polymorphisms (tagSNPs) in genes encoding for DHCR7, CYP2R1, VDBP, CYP27B1, CYP27A1, CYP24A1, VDR and RXRG, and obesity traits in 5224 participants (aged 45 years) in the 1958 British birth cohort (1958BC). We further extended our analyses to investigate the associations between SNPs and obesity traits using the summary statistics from the GIANT (Genetic Investigation of Anthropometric Traits) consortium (n=123 865).

Results:

In the 1958BC (n=5224), after Bonferroni correction, none of the tagSNPs were associated with obesity traits except for one tagSNP from CYP24A1 that was associated with waist–hip ratio (WHR) (rs2296239, P=0.001). However, the CYP24A1 SNP was not associated with BMI-adjusted WHR (WHRadj) in the 1958BC (rs2296239, P=1.00) and GIANT results (n=123 865, P=0.18). There was also no evidence for an interaction between the tagSNPs and obesity on BMI, WC, WHR and WHRadj in the 1958BC. In the GIANT consortium, none of the tagSNPs were associated with obesity traits.

Conclusions:

Despite a very large study, our findings suggest that the vitamin D pathway genes are unlikely to have a major role in obesity-related traits in the general population.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Flegal KM, Carroll MD, Ogden CL, Curtin LR . Prevalence and trends in obesity among US adults, 1999–2008. JAMA 2010; 303: 235–241.

    CAS  PubMed  Google Scholar 

  2. Berghofer A, Pischon T, Reinhold T, Apovian CM, Sharma AM, Willich SN . Obesity prevalence from a European perspective: a systematic review. BMC Public Health 2008; 8: 200.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Earthman CP, Beckman LM, Masodkar K, Sibley SD . The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications. Int J Obes (Lond) 2012; 36: 387–396.

    Article  CAS  Google Scholar 

  4. Foss YJ . Vitamin D deficiency is the cause of common obesity. Med Hypotheses 2009; 72: 314–321.

    Article  CAS  PubMed  Google Scholar 

  5. Holick MF, Chen TC . Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 2008; 87: 1080S–1086SS.

    Article  CAS  PubMed  Google Scholar 

  6. Berry D, Hyppönen E . Determinants of vitamin D status: focus on genetic variations. Curr Opin Nephrol Hypertens 2011; 20: 331–336.

    Article  CAS  PubMed  Google Scholar 

  7. Jiang H, Xiong DH, Guo YF, Shen H, Xiao P, Yang F et al. Association analysis of vitamin D-binding protein gene polymorphisms with variations of obesity-related traits in Caucasian nuclear families. Int J Obes (Lond) 2007; 31: 1319–1324.

    Article  CAS  Google Scholar 

  8. Hirai M, Suzuki S, Hinokio Y, Hirai A, Chiba M, Akai H et al. Variations in vitamin D-binding protein (group-specific component protein) are associated with fasting plasma insulin levels in Japanese with normal glucose tolerance. J Clin Endocrinol Metab 2000; 85: 1951–1953.

    CAS  PubMed  Google Scholar 

  9. Malecki MT, Klupa T, Wolkow P, Bochenski J, Wanic K, Sieradzki J . Association study of the vitamin D: 1alpha-hydroxylase (CYP1alpha) gene and type 2 diabetes mellitus in a Polish population. Diabetes Metab 2003; 29: 119–124.

    Article  CAS  PubMed  Google Scholar 

  10. Ochs-Balcom HM, Chennamaneni R, Millen AE, Shields PG, Marian C, Trevisan M et al. Vitamin D receptor gene polymorphisms are associated with adiposity phenotypes. Am J Clin Nutr 2011; 93: 5–10.

    Article  CAS  PubMed  Google Scholar 

  11. Dorjgochoo T, Shi J, Gao YT, Long J, Delahanty R, Xiang YB et al. Genetic variants in vitamin D metabolism-related genes and body mass index: analysis of genome-wide scan data of approximately 7000 Chinese women. Int J Obes (Lond) 2012; 36: 1252–1255.

    Article  CAS  Google Scholar 

  12. Bosse Y, Lemire M, Poon AH, Daley D, He JQ, Sandford A et al. Asthma and genes encoding components of the vitamin D pathway. Respir Res 2009; 10: 98.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU et al. Association analyses of 249 796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937–948.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lindgren CM, Heid IM, Randall JC, Lamina C, Steinthorsdottir V, Qi L et al. Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet 2009; 5: e1000508.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Power C, Atherton K, Strachan DP, Shepherd P, Fuller E, Davis A et al. Life-course influences on health in British adults: effects of socio-economic position in childhood and adulthood. Int J Epidemiol 2007; 36: 532–539.

    Article  PubMed  Google Scholar 

  16. Power C, Elliott J . Cohort profile: 1958 British birth cohort (National Child Development Study). Int J Epidemiol 2006; 35: 34–41.

    Article  PubMed  Google Scholar 

  17. Atherton K, Fuller E, Shepherd P, Strachan DP, Power C . Loss and representativeness in a biomedical survey at age 45 years: 1958 British birth cohort. J Epidemiol Community Health 2008; 62: 216–223.

    Article  CAS  PubMed  Google Scholar 

  18. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  PubMed  Google Scholar 

  19. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.

  20. Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 2009; 41: 703–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000; 894: 1–253.

  22. Smith GD, Ebrahim S . Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 2004; 33: 30–42.

    Article  PubMed  Google Scholar 

  23. Berry DJ, Vimaleswaran KS, Whittaker JC, Hingorani AD, Hyppönen E . Evaluation of genetic markers as instruments for mendelian randomization studies on vitamin D. PLoS One 2012; 7: e37465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 2010; 376: 180–188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Narvaez CJ, Matthews D, Broun E, Chan M, Welsh J . Lean phenotype and resistance to diet-induced obesity in vitamin D receptor knockout mice correlates with induction of uncoupling protein-1 in white adipose tissue. Endocrinology 2009; 150: 651–661.

    Article  CAS  PubMed  Google Scholar 

  26. Ochs-Balcom HM, Cicek MS, Thompson CL, Tucker TC, Elston RC, JP S et al. Association of vitamin D receptor gene variants, adiposity and colon cancer. Carcinogenesis 2008; 29: 1788–1793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ye WZ, Reis AF, Dubois-Laforgue D, Bellanne-Chantelot C, Timsit J, Velho G . Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset. Eur J Endocrinol 2001; 145: 181–186.

    Article  CAS  PubMed  Google Scholar 

  28. Barger-Lux MJ, Heaney RP, Hayes J, DeLuca HF, Johnson ML, Gong G . Vitamin D receptor gene polymorphism, bone mass, body size, and vitamin D receptor density. Calcif Tissue Int 1995; 57: 161–162.

    Article  CAS  PubMed  Google Scholar 

  29. Filus A, Trzmiel A, Kuliczkowska-Plaksej J, Tworowska U, Jedrzejuk D, Milewicz A et al. Relationship between vitamin D receptor BsmI and FokI polymorphisms and anthropometric and biochemical parameters describing metabolic syndrome. Aging Male 2008; 11: 134–139.

    Article  CAS  PubMed  Google Scholar 

  30. Tworowska-Bardzinska U, Lwow F, Kubicka E, Laczmanski L, Jedzrzejuk D, Dunajska K et al. The vitamin D receptor gene BsmI polymorphism is not associated with anthropometric and biochemical parameters describing metabolic syndrome in postmenopausal women. Gynecol Endocrinol 2008; 24: 514–518.

    Article  CAS  PubMed  Google Scholar 

  31. Ioannidis JP, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG . Genetic associations in large versus small studies: an empirical assessment. Lancet 2003; 361: 567–571.

    Article  PubMed  Google Scholar 

  32. Jones G, Prosser DE . The activating enzymes of vitamin D metabolism (25- and 1alpha- hydroxylases). In: Feldman D, Pike JW, Adams JS, (eds) Vitamin D vol. 1. Elsevier Academic Press: London, UK; Waltham, MA, USA; San Diego, CA, USA, 2011. pp 23–42.

    Chapter  Google Scholar 

  33. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K . A comprehensive review of genetic association studies. Genet Med 2002; 4: 45–61.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Centre for Longitudinal studies, Institute of Education (original data producers) for providing the data. The Medical Research Council funded the 2002–2004 clinical follow-up of the 1958 birth cohort (grant G0000934). We also thank Ruth JF Loos for providing the summary results from the GIANT consortium. This work was undertaken at the Centre for Paediatric Epidemiology and Biostatistics, which benefits from funding support from the MRC in its capacity as the MRC Centre of Epidemiology for Child Health. Research at the University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from R&D funding received from the NHS Executive. Funding for the project was provided by the British Heart Foundation (grant PG/09/023), Academy of Finland (project 139900), the PrevMetSyn/Salve project from Academy of Finland/MRC and the UK Medical Research Council (grant G0601653). Further support was obtained from the ENGAGE project and grant agreement HEALTH-F4-2007-201413.

Disclaimer

The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. JW is the Director of Statistical Genetics at GlaxoSmithKline. The company had no role in the production of the paper, development or interpretation of the study questions or in the decision to submit for publication.

Author information

Authors and Affiliations

  1. Centre for Paediatric Epidemiology and Biostatistics, MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London, UK

    K S Vimaleswaran, A Cavadino, D J Berry, C Power & E Hyppönen

  2. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK

    J C Whittaker

  3. Department of Epidemiology and Biostatistics Imperial College London, School of Public Health, London, UK

    M-R Järvelin

  4. MRC-HPA Centre for Environment and Health, Imperial College, Faculty of Medicine, London, UK

    M-R Järvelin

  5. Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland

    M-R Järvelin

  6. Institute of Health Sciences, University of Oulu, and Biocenter Oulu, University of Oulu, Universitranisy of Oulu, Oulu, Finland

    M-R Järvelin

Authors
  1. K S Vimaleswaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Cavadino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D J Berry
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J C Whittaker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Power
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M-R Järvelin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E Hyppönen
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

The Genetic Investigation of Anthropometric Traits (GIANT) Consortium

Corresponding author

Correspondence to K S Vimaleswaran.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vimaleswaran, K., Cavadino, A., Berry, D. et al. Genetic association analysis of vitamin D pathway with obesity traits. Int J Obes 37, 1399–1406 (2013). https://doi.org/10.1038/ijo.2013.6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2013.6

Keywords

This article is cited by

Search

Advanced search

Quick links