Skip to main content
SpringerLink
Log in

Genome-wide association analysis of circulating vitamin D levels in children with asthma

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Vitamin D deficiency is becoming more apparent in many populations. Genetic factors may play a role in the maintenance of vitamin D levels. The objective of this study was to perform a genome-wide analysis (GWAS) of vitamin D levels, including replication of prior GWAS results. We measured 25-hydroxyvitamin D (25(OH)D) levels in serum collected at the time of enrollment and at year 4 in 572 Caucasian children with asthma, who were part of a multi-center clinical trial, the Childhood Asthma Management Program. Replication was performed in a second cohort of 592 asthmatics from Costa Rica and a third cohort of 516 Puerto Rican asthmatics. In addition, we attempted replication of three SNPs that were previously identified in a large GWAS of Caucasian individuals. The setting included data from a clinical trial of childhood asthmatics and two cohorts of asthmatics recruited for genetic studies of asthma. The main outcome measure was circulating 25(OH)D levels. The 25(OH)D levels at the two time-points were only modestly correlated with each other (intraclass correlation coefficient = 0.33) in the CAMP population. We identified SNPs that were nominally associated with 25(OH)D levels at two time-points in CAMP, and replicated four SNPs in the Costa Rican cohort: rs11002969, rs163221, rs1678849, and rs4864976. However, these SNPs were not significantly associated with 25(OH)D levels in a third population of Puerto Rican asthmatics. We were able to replicate the SNP with the strongest effect, previously reported in a large GWAS: rs2282679 (GC), and we were able to replicate another SNP, rs10741657 (CYP2R1), to a lesser degree. We were able to replicate two of three prior significant findings in a GWAS of 25(OH)D levels. Other SNPs may be additionally associated with 25(OH)D levels in certain populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • (1999a) The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Childhood Asthma Management Program Research Group. Control Clin Trials 20: 91–120

  • (1999b) Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group. Diabetologia 42:51–54

  • Agborsangaya C, Toriola AT, Grankvist K, Surcel HM, Holl K, Parkkila S, Tuohimaa P, Lukanova A, Lehtinen M (2010) The effects of storage time and sampling season on the stability of serum 25-hydroxy vitamin D and androstenedione. Nutr Cancer 62:51–57

    Article  PubMed  CAS  Google Scholar 

  • Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB, Li Q, Weinstein SJ, Purdue M, Virtamo J, Horst R, Wheeler W, Chanock S, Hunter DJ, Hayes RB, Kraft P, Albanes D (2010) Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19:2739–2745

    Article  PubMed  CAS  Google Scholar 

  • Bird HR, Canino GJ, Davies M, Duarte CS, Febo V, Ramirez R, Hoven C, Wicks J, Musa G, Loeber R (2006) A study of disruptive behavior disorders in Puerto Rican youth: I. Background, design, and survey methods. J Am Acad Child Adolesc Psychiatry 45:1032–1041

    Article  PubMed  Google Scholar 

  • Brehm JM, Celedon JC, Soto-Quiros ME, Avila L, Hunninghake GM, Forno E, Laskey D, Sylvia JS, Hollis BW, Weiss ST, Litonjua AA (2009) Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med 179:765–771

    Article  PubMed  CAS  Google Scholar 

  • Brehm JM, Schuemann BS, Fuhlbrigge AL, Hollis BW, Strunk RC, Zeiger RS, Weiss ST, Litonjua AA (2010) Serum vitamin D levels and severe asthma exacerbations in the childhood asthma management program study. J Allergy Clin Immun 126(1):52–58

    Article  PubMed  CAS  Google Scholar 

  • Celedon JC, Soto-Quiros ME, Palmer LJ, Senter J, Mosley J, Silverman EK, Weiss ST (2002) Lack of association between a polymorphism in the interleukin-13 gene and total serum immunoglobulin E level among nuclear families in Costa Rica. Clin Exp Allergy 32:387–390

    Article  PubMed  CAS  Google Scholar 

  • Engelman CD, Fingerlin TE, Langefeld CD, Hicks PJ, Rich SS, Wagenknecht LE, Bowden DW, Norris JM (2008) Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans. J Clin Endocrinol Metab 93:3381–3388

    Article  PubMed  CAS  Google Scholar 

  • Engelman CD, Meyers KJ, Ziegler JT, Taylor KD, Palmer ND, Haffner SM, Fingerlin TE, Wagenknecht LE, Rotter JI, Bowden DW, Langefeld CD, Norris JM (2010) Genome-wide association study of vitamin D concentrations in Hispanic Americans: the IRAS family study. J Steroid Biochem Mol Biol 122:186–192

    Article  PubMed  CAS  Google Scholar 

  • Escamilla MA, Spesny M, Reus VI, Gallegos A, Meza L, Molina J, Sandkuijl LA, Fournier E, Leon PE, Smith LB, Freimer NB (1996) Use of linkage disequilibrium approaches to map genes for bipolar disorder in the Costa Rican population. Am J Med Genet 67:244–253

    Article  PubMed  CAS  Google Scholar 

  • Giovannucci E (2005) The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control 16:83–95

    Article  PubMed  Google Scholar 

  • Giovannucci E (2006) The epidemiology of vitamin D and colorectal cancer: recent findings. Curr Opin Gastroenterol 22:24–29

    Article  PubMed  CAS  Google Scholar 

  • Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M, Newmark HL, Giovannucci E, Wei M, Holick MF (2005) Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol 97:179–194

    Article  PubMed  CAS  Google Scholar 

  • Grant WB (2006) Epidemiology of disease risks in relation to vitamin D insufficiency. Prog Biophys Mol Biol 92:65–79

    Article  PubMed  CAS  Google Scholar 

  • Heaney RP (2003) Long-latency deficiency disease: insights from calcium and vitamin D. Am J Clin Nutr 78:912–919

    PubMed  CAS  Google Scholar 

  • Heaney RP (2004) Functional indices of vitamin D status and ramifications of vitamin D deficiency. Am J Clin Nutr 80:1706S–1709S

    PubMed  CAS  Google Scholar 

  • Holick MF (2005) 25-OH-vitamin D assays. J Clin Endocrinol Metab 90:3128–3129

    Article  PubMed  CAS  Google Scholar 

  • Holick MF (2006) High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 81:353–373

    Article  PubMed  CAS  Google Scholar 

  • Hollis BW (2005) Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 135:317–322

    PubMed  CAS  Google Scholar 

  • Hollis BW, Napoli JL (1985) Improved radioimmunoassay for vitamin D and its use in assessing vitamin D status. Clin Chem 31:1815–1819

    PubMed  CAS  Google Scholar 

  • Hollis BW, Wagner CL (2005) Normal serum vitamin D levels. N Engl J Med 352:515–516

    PubMed  CAS  Google Scholar 

  • Hollis BW, Kamerud JQ, Selvaag SR, Lorenz JD, Napoli JL (1993) Determination of vitamin D status by radioimmunoassay with an 125I-labeled tracer. Clin Chem 39:529–533

    PubMed  CAS  Google Scholar 

  • Hollis BW, Wagner CL, Drezner MK, Binkley NC (2007) Circulating vitamin D(3) and 25-hydroxyvitamin D in humans: an important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol 103(3–5):631–634

    Article  PubMed  CAS  Google Scholar 

  • Hunninghake GM, Soto-Quiros ME, Avila L, Su J, Murphy A, Demeo DL, Ly NP, Liang C, Sylvia JS, Klanderman BJ, Lange C, Raby BA, Silverman EK, Celedon JC (2007) Polymorphisms in IL13, total IgE, eosinophilia, and asthma exacerbations in childhood. J Allergy Clin Immunol 120:84–90

    Article  PubMed  CAS  Google Scholar 

  • Hunter D, De Lange M, Snieder H, MacGregor AJ, Swaminathan R, Thakker RV, Spector TD (2001) Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation. J Bone Miner Res 16:371–378

    Article  PubMed  CAS  Google Scholar 

  • Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM (2001) Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358:1500–1503

    Article  PubMed  CAS  Google Scholar 

  • Karohl C, Su S, Kumari M, Tangpricha V, Veledar E, Vaccarino V, Raggi P (2010) Heritability and seasonal variability of vitamin D concentrations in male twins. Am J Clin Nutr 92:1393–1398

    Article  PubMed  CAS  Google Scholar 

  • Lamberg-Allardt C (2006) Vitamin D in foods and as supplements. Prog Biophys Mol Biol 92:33–38

    Article  PubMed  CAS  Google Scholar 

  • Lee AB, Luca D, Klei L, Devlin B, Roeder K (2010) Discovering genetic ancestry using spectral graph theory. Genet Epidemiol 34:51–59

    Article  PubMed  CAS  Google Scholar 

  • Litonjua AA, Weiss ST (2007) Is vitamin D deficiency to blame for the asthma epidemic? J Allergy Clin Immunol 120:1031–1035

    Article  PubMed  CAS  Google Scholar 

  • Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG (2004) Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum 50:72–77

    Article  PubMed  CAS  Google Scholar 

  • Nesby-O’Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, Allen C, Doughertly C, Gunter EW, Bowman BA (2002) Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988–1994. Am J Clin Nutr 76:187–192

    PubMed  Google Scholar 

  • Oliphant A, Barker DL, Stuelpnagel JR, Chee MS (2002) BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping. Biotechniques Suppl 56–8:60–61

    Google Scholar 

  • Orton SM, Morris AP, Herrera BM, Ramagopalan SV, Lincoln MR, Chao MJ, Vieth R, Sadovnick AD, Ebers GC (2008) Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis. Am J Clin Nutr 88:441–447

    PubMed  CAS  Google Scholar 

  • Poon AH, Laprise C, Lemire M, Montpetit A, Sinnett D, Schurr E, Hudson TJ (2004) Association of vitamin D receptor genetic variants with susceptibility to asthma and atopy. Am J Respir Crit Care Med 170:967–973

    Article  PubMed  Google Scholar 

  • Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909

    Article  PubMed  CAS  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  PubMed  CAS  Google Scholar 

  • Raby BA, Lazarus R, Silverman EK, Lake S, Lange C, Wjst M, Weiss ST (2004) Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am J Respir Crit Care Med 170:1057–1065

    Article  PubMed  Google Scholar 

  • Ramos-Lopez E, Bruck P, Jansen T, Herwig J, Badenhoop K (2007) CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes Metab Res Rev 23:631–636

    Article  PubMed  CAS  Google Scholar 

  • Sahota H, Barnett H, Lesosky M, Raboud JM, Vieth R, Knight JA (2008) Association of vitamin D related information from a telephone interview with 25-hydroxyvitamin D. Cancer Epidemiol Biomarkers Prev 17:232–238

    Article  PubMed  CAS  Google Scholar 

  • Shea MK, Benjamin EJ, Dupuis J, Massaro JM, Jacques PF, D’Agostino RB Sr, Ordovas JM, O’Donnell CJ, Dawson-Hughes B, Vasan RS, Booth SL (2009) Genetic and non-genetic correlates of vitamins K and D. Eur J Clin Nutr 63:458–464

    Article  PubMed  CAS  Google Scholar 

  • Taback SP, Simons FE (2007) Anaphylaxis and vitamin D: a role for the sunshine hormone? J Allergy Clin Immunol 120:128–130

    Article  PubMed  CAS  Google Scholar 

  • Tang H, Choudhry S, Mei R, Morgan M, Rodriguez-Cintron W, Burchard EG, Risch NJ (2007) Recent genetic selection in the ancestral admixture of Puerto Ricans. Am J Hum Genet 81:626–633

    Article  PubMed  CAS  Google Scholar 

  • van der Mei IA, Blizzard L, Ponsonby AL, Dwyer T (2006) Validity and reliability of adult recall of past sun exposure in a case-control study of multiple sclerosis. Cancer Epidemiol Biomarkers Prev 15:1538–1544

    Article  PubMed  Google Scholar 

  • Vollmert C, Illig T, Altmuller J, Klugbauer S, Loesgen S, Dumitrescu L, Wjst M (2004) Single nucleotide polymorphism screening and association analysis–exclusion of integrin beta 7 and vitamin D receptor (chromosome 12q) as candidate genes for asthma. Clin Exp Allergy 34:1841–1850

    Article  PubMed  CAS  Google Scholar 

  • Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O’Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Jarvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hypponen E, Spector TD (2010) Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376(9736):180–188

    Article  PubMed  CAS  Google Scholar 

  • Webb AR (2006) Who, what, where and when-influences on cutaneous vitamin D synthesis. Prog Biophys Mol Biol 92:17–25

    Article  PubMed  CAS  Google Scholar 

  • Wjst M (2005) Variants in the vitamin D receptor gene and asthma. BMC Genet 6:2

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge the CAMP investigators and research team, supported by NHLBI, for collection of CAMP Genetic Ancillary Study data. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham and Women’s Hospital under appropriate CAMP policies and human subject’s protections. This work was funded by R21 HL089842 from the National Heart, Lung and Blood Institute, National Institutes of Health. The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, and T32 HL07427 from the National Heart, Lung and Blood Institute, National Institutes of Health.

Author information

Authors and Affiliations

  1. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA

    Jessica Lasky-Su, Nancy Lange, Scott T. Weiss & Augusto A. Litonjua

  2. Harvard Medical School, Boston, MA, USA

    Jessica Lasky-Su, Nancy Lange, Scott T. Weiss & Augusto A. Litonjua

  3. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Nancy Lange & Augusto A. Litonjua

  4. Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA

    John M. Brehm & Juan C. Celedón

  5. Novartis Institutes for Biomedical Research, Cambridge, MA, USA

    Amy Damask

  6. Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica

    Manuel Soto-Quiros & Lydiana Avila

  7. Behavioral Sciences Institute, University of Puerto Rico, San Juan, PR, USA

    Glorisa Canino

  8. University of Connecticut Health Center, Farmington, CT, USA

    Michelle M. Cloutier

  9. Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC, USA

    Bruce W. Hollis

  10. Department of Medicine, Center for Genomic Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Scott T. Weiss

Authors
  1. Jessica Lasky-Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nancy Lange
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John M. Brehm
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amy Damask
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manuel Soto-Quiros
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lydiana Avila
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan C. Celedón
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Glorisa Canino
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michelle M. Cloutier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bruce W. Hollis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Scott T. Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Augusto A. Litonjua
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Augusto A. Litonjua.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 35 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lasky-Su, J., Lange, N., Brehm, J.M. et al. Genome-wide association analysis of circulating vitamin D levels in children with asthma. Hum Genet 131, 1495–1505 (2012). https://doi.org/10.1007/s00439-012-1185-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-012-1185-z

Keywords

Search

Navigation