, Volume 57, Issue 6, pp 1159–1172 | Cite as

A serum 25-hydroxyvitamin D concentration-associated genetic variant in DHCR7 interacts with type 2 diabetes status to influence subclinical atherosclerosis (measured by carotid intima–media thickness)

  • Rona J. StrawbridgeEmail author
  • Anna Deleskog
  • Olga McLeod
  • Lasse Folkersen
  • Maryam Kavousi
  • Karl Gertow
  • Damiano Baldassarre
  • Fabrizio Veglia
  • Karin Leander
  • Bruna Gigante
  • Jussi Kauhanen
  • Rainer Rauramaa
  • Andries J. Smit
  • Elmo Mannarino
  • Philippe Giral
  • Abbas Dehghan
  • Albert Hofman
  • Oscar H. Franco
  • Steve E. Humphries
  • Elena Tremoli
  • Ulf de Faire
  • Sven Gustafsson
  • Claes-Göran Östensson
  • Per Eriksson
  • John Öhrvik
  • Anders Hamsten



The findings of studies investigating whether or not low serum 25-hydroxyvitamin D [25(OH)D] concentration promotes development of atherosclerosis have been contradictory. The present study employed a Mendelian randomisation approach and carotid artery intima–media thickness (cIMT), a surrogate marker of coronary artery disease, to address this question.


The multicentre, longitudinal Carotid Intima–Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population (IMPROVE) cohort study, which enrolled individuals with at least three cardiovascular risk factors and no history or symptoms of cardiovascular disease, was used for the present investigation. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30. Six single nucleotide polymorphisms (SNPs) associated with serum 25(OH)D concentration in genome-wide association studies were identified and genotyped in 3,418 individuals, of whom 929 had type 2 diabetes.


SNPs in the genes encoding vitamin D binding protein (GC; rs2282679 and rs7041) and 7-dehydrocholesterol reductase/NAD synthetase-1 (DHCR7; rs12785878 and rs3829251) were negatively associated with 25(OH)D levels. Effect sizes and significance of associations between SNPs and 25(OH)D levels differed between individuals with and without type 2 diabetes, although no significant interactions were observed. A SNP in DHCR7 interacted with type 2 diabetes to significantly influence progression of cIMT measures independent of 25(OH)D levels and established risk factors. Expression analysis demonstrated that this SNP modulates DHCR7 mRNA levels in aortic adventitia.


SNPs in GC and DHCR7 were associated with serum levels of 25(OH)D, but only rs3829251 (DHCR7) influenced progression of subclinical atherosclerosis, as measured by cIMT, in a manner dependent on type 2 diabetes status but independent of 25(OH)D levels.


Carotid intima–media thickness Genetic variant Interaction Subclinical atherosclerosis Type 2 diabetes Vitamin D 



1,25-Dihydroxyvitamin D


25-Hydroxyvitamin D


Advanced Study of Aortic Pathology


Maximum intima–media thickness of the bifurcation


Mean intima–media thickness of the bifurcation


Maximum intima–media thickness of the common carotid artery


Mean intima–media thickness of the common carotid artery


Carotid intima–media thickness


C-reactive protein


Cardiovascular disease


Carotid Intima–Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population


Maximum intima–media thickness of the entire carotid tree


Mean intima–media thickness of the entire carotid tree


Mean of the IMTmax


Single nucleotide polymorphisms


Vitamin D receptor



The IMPROVE study was supported by the European Commission (Contract number: QLG1-CT-2002-00896), Swedish Heart-Lung Foundation, Swedish Research Council (projects 8691 and 0593), Knut and Alice Wallenberg Foundation, Foundation for Strategic Research, Stockholm County Council (project 592229), Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and Stockholm County Council, European Union Framework Programme 7 (FP7/2007-2013) for Innovative Medicine Initiative (no. IMI/115006 [the SUMMIT consortium]), Magnus Bergwall Foundation, Academy of Finland (grant no. 110413), British Heart Foundation (RG2008/08, RG2008/014) and the Italian Ministry of Health (Ricerca Corrente). The Rotterdam genome-wide association study was funded by the Netherlands Organisation of Scientific Research (NWO) Investments (no. 175.010.2005.011, 911-03-012), Research Institute for Diseases in the Elderly (RIDE; 014-93-015), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Ageing (NCHA) project no. 050-060-810. The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organisation for the Health Research and Development (ZonMw), RIDE, Netherlands Heart Foundation, Ministry of Education, Culture, and Science, Ministry for Health, Welfare, and Sports, European Commission (DG XII), and the Municipality of Rotterdam. Maryam Kavousi is supported by the AXA Research Fund. Abbas Dehghan is supported by NWO grant (veni, 916.12.154) and EUR Fellowship. Oscar H. Franco works in ErasmusAGE, a centre funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc. and AXA.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript. Nestlé Nutrition (Nestec Ltd.), Metagenics Inc. and AXA had no role in the design and conduct of the study, the collection, management, analysis and interpretation of the data, or in the preparation, review or approval of the manuscript.


This study was conceived by AHa, SG and C-GÖ, designed by RJS, ADel and JÖ, and analysis was performed by RJS, ADel, LF, MK and JÖ. KL and BG contributed to interpretation of the data. Data acquisition was carried out by OM, KG, ADeh, AHo, OHF, the IMPROVE study group (DB, FV, JK, RR, AJS, EM, PG, SFH, ET, UdF), the Rotterdam Study group (ADeh, AHo, OHF) PE and AHa. RJS is responsible for the integrity of the work as a whole. All authors have contributed to drafting and critically revising the manuscript and have approved the final draft for publication.

Supplementary material

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  1. 1.
    Forouhi NG, Ye Z, Rickard AP et al (2012) Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. Diabetologia 55:2173–2182PubMedCrossRefGoogle Scholar
  2. 2.
    Grandi NC, Breitling LP, Brenner H (2010) Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies. Prev Med 51:228–233PubMedCrossRefGoogle Scholar
  3. 3.
    Baz-Hecht M, Goldfine AB (2010) The impact of vitamin D deficiency on diabetes and cardiovascular risk. Curr Opin Endocrinol Diabetes Obes 17:113–119PubMedCrossRefGoogle Scholar
  4. 4.
    Nagpal S, Na S, Rathnachalam R (2005) Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 26:662–687PubMedCrossRefGoogle Scholar
  5. 5.
    Zittermann A, Schleithoff SS, Koerfer R (2005) Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr 94:483–492PubMedCrossRefGoogle Scholar
  6. 6.
    Mathieu C, Gysemans C, Giulietti A, Bouillon R (2005) Vitamin D and diabetes. Diabetologia 48:1247–1257PubMedCrossRefGoogle Scholar
  7. 7.
    Pilz S, Tomaschitz A, Ritz E, Pieber TR (2009) Vitamin D status and arterial hypertension: a systematic review. Nat Rev Cardiol 6:621–630PubMedCrossRefGoogle Scholar
  8. 8.
    Pilz S, Tomaschitz A, Marz W et al (2011) Vitamin D, cardiovascular disease and mortality. Clin Endocrinol 75:575–584CrossRefGoogle Scholar
  9. 9.
    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281PubMedCrossRefGoogle Scholar
  10. 10.
    Berry D, Hypponen E (2011) Determinants of vitamin D status: focus on genetic variations. Curr Opin Nephrol Hypertens 20:331–336PubMedCrossRefGoogle Scholar
  11. 11.
    Wang TJ, Zhang F, Richards JB et al (2010) Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376:180–188PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Ahn J, Yu K, Stolzenberg-Solomon R et al (2010) Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19:2739–2745PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    McGrath JJ, Saha S, Burne TH, Eyles DW (2010) A systematic review of the association between common single nucleotide polymorphisms and 25-hydroxyvitamin D concentrations. J Steroid Biochem Mol Biol 121:471–477PubMedCrossRefGoogle Scholar
  14. 14.
    Hunter D, de Lange M, Snieder H et al (2001) Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation. J Bone Miner Res Off J Am Soc Bone Miner Res 16:371–378CrossRefGoogle Scholar
  15. 15.
    Shea MK, Benjamin EJ, Dupuis J et al (2009) Genetic and non-genetic correlates of vitamins K and D. Eur J Clin Nutr 63:458–464PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Amato M, Montorsi P, Ravani A et al (2007) Carotid intima-media thickness by B-mode ultrasound as surrogate of coronary atherosclerosis: correlation with quantitative coronary angiography and coronary intravascular ultrasound findings. Eur Heart J 28:2094–2101PubMedCrossRefGoogle Scholar
  17. 17.
    O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr (1999) Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340:14–22PubMedCrossRefGoogle Scholar
  18. 18.
    Chambless LE, Heiss G, Folsom AR et al (1997) Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol 146:483–494PubMedCrossRefGoogle Scholar
  19. 19.
    Baldassarre D, Nyyssonen K, Rauramaa R et al (2010) Cross-sectional analysis of baseline data to identify the major determinants of carotid intima-media thickness in a European population: the IMPROVE study. Eur Heart J 31:614–622PubMedCrossRefGoogle Scholar
  20. 20.
    Deleskog A, Piksasova O, Silveira A et al (2013) Serum 25-hydroxyvitamin D concentration in subclinical carotid atherosclerosis. Arterioscler Thromb Vasc Biol 33:2633–2638PubMedCrossRefGoogle Scholar
  21. 21.
    Bots ML, Hoes AW, Koudstaal PJ, Hofman A, de Grobbee (1997) Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 96:1432–1437PubMedCrossRefGoogle Scholar
  22. 22.
    Hofman A, van Duijn CM, Franco OH et al (2011) The Rotterdam Study: 2012 objectives and design update. Eur J Epidemiol 26:657–686PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Odink AE, van der Lugt A, Hofman A et al (2010) Risk factors for coronary, aortic arch and carotid calcification; the Rotterdam Study. J Hum Hypertens 24:86–92PubMedCrossRefGoogle Scholar
  24. 24.
    Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R (1990) Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15:827–832PubMedCrossRefGoogle Scholar
  25. 25.
    Trynka G, Hunt KA, Bockett NA et al (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 43:1193–1201PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Folkersen L, van't Hooft F, Chernogubova E et al (2010) Association of genetic risk variants with expression of proximal genes identifies novel susceptibility genes for cardiovascular disease. Circ Cardiovasc Genet 3:365–373PubMedCrossRefGoogle Scholar
  28. 28.
    Targher G, Bertolini L, Padovani R et al (2006) Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Clin Endocrinol 65:593–597CrossRefGoogle Scholar
  29. 29.
    Reis JP, von Muhlen D, Michos ED et al (2009) Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis. Atherosclerosis 207:585–590PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Michos ED, Streeten EA, Ryan KA et al (2009) Serum 25-hydroxyvitamin d levels are not associated with subclinical vascular disease or C-reactive protein in the old order amish. Calcif Tissue Int 84:195–202PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Carrelli AL, Walker MD, Lowe H et al (2011) Vitamin D deficiency is associated with subclinical carotid atherosclerosis: the Northern Manhattan study. Stroke J Cereb Circ 42:2240–2245CrossRefGoogle Scholar
  32. 32.
    Bis JC, Kavousi M, Franceschini N et al (2011) Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. Nat Genet 43:940–947PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Teslovich TM, Musunuru K, Smith AV et al (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466:707–713PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Scragg R, Sowers M, Bell C, Third National H, Nutrition Examination S (2004) Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care 27:2813–2818PubMedCrossRefGoogle Scholar
  35. 35.
    Ford ES, Ajani UA, McGuire LC, Liu S (2005) Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care 28:1228–1230PubMedCrossRefGoogle Scholar
  36. 36.
    Martins D, Wolf M, Pan D et al (2007) Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 167:1159–1165PubMedCrossRefGoogle Scholar
  37. 37.
    Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF (2000) Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 72:690–693PubMedGoogle Scholar
  38. 38.
    Deleskog A, Hilding A, Brismar K, Hamsten A, Efendic S, Ostenson CG (2012) Low serum 25-hydroxyvitamin D level predicts progression to type 2 diabetes in individuals with prediabetes but not with normal glucose tolerance. Diabetologia 55:1668–1678PubMedCrossRefGoogle Scholar
  39. 39.
    de Boer IH, Kestenbaum B, Shoben AB, Michos ED, Sarnak MJ, Siscovick DS (2009) 25-Hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification. J Am Soc Nephrol JASN 20:1805–1812CrossRefGoogle Scholar
  40. 40.
    Somjen D, Weisman Y, Kohen F et al (2005) 25-Hydroxyvitamin D3-1alpha-hydroxylase is expressed in human vascular smooth muscle cells and is upregulated by parathyroid hormone and estrogenic compounds. Circulation 111:1666–1671PubMedCrossRefGoogle Scholar
  41. 41.
    Wu-Wong JR (2009) Potential for vitamin D receptor agonists in the treatment of cardiovascular disease. Br J Pharmacol 158:395–412PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Oh J, Weng S, Felton SK et al (2009) 1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Circulation 120:687–698PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Ohsawa M, Koyama T, Yamamoto K, Hirosawa S, Kamei S, Kamiyama R (2000) 1alpha,25-Dihydroxyvitamin D(3) and its potent synthetic analogs downregulate tissue factor and upregulate thrombomodulin expression in monocytic cells, counteracting the effects of tumor necrosis factor and oxidized LDL. Circulation 102:2867–2872PubMedCrossRefGoogle Scholar
  44. 44.
    Richart T, Li Y, Staessen JA (2007) Renal versus extrarenal activation of vitamin D in relation to atherosclerosis, arterial stiffening, and hypertension. Am J Hypertens 20:1007–1015PubMedCrossRefGoogle Scholar
  45. 45.
    Zittermann A, Schleithoff SS, Koerfer R (2007) Vitamin D and vascular calcification. Curr Opin Lipidol 18:41–46PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Rona J. Strawbridge
    • 1
    Email author
  • Anna Deleskog
    • 1
    • 2
  • Olga McLeod
    • 1
  • Lasse Folkersen
    • 1
  • Maryam Kavousi
    • 3
    • 4
  • Karl Gertow
    • 1
  • Damiano Baldassarre
    • 5
  • Fabrizio Veglia
    • 5
  • Karin Leander
    • 6
  • Bruna Gigante
    • 6
  • Jussi Kauhanen
    • 7
  • Rainer Rauramaa
    • 8
  • Andries J. Smit
    • 4
    • 9
  • Elmo Mannarino
    • 10
  • Philippe Giral
    • 11
  • Abbas Dehghan
    • 3
    • 4
  • Albert Hofman
    • 3
    • 4
  • Oscar H. Franco
    • 3
    • 4
  • Steve E. Humphries
    • 12
  • Elena Tremoli
    • 5
  • Ulf de Faire
    • 6
  • Sven Gustafsson
    • 2
  • Claes-Göran Östensson
    • 2
  • Per Eriksson
    • 1
  • John Öhrvik
    • 1
  • Anders Hamsten
    • 1
  1. 1.Atherosclerosis Research Unit, Centre for Molecular Medicine, Building L8:03Karolinska University Hospital SolnaStockholmSweden
  2. 2.Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
  3. 3.Department of EpidemiologyErasmus University Medical CenterRotterdamThe Netherlands
  4. 4.Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy AgeingRotterdamThe Netherlands
  5. 5.Dipartimento di Scienze Farmacologiche e BiomolecolariUniversità di Milano & Centro Cardiologico Monzino, IRCCSMilanItaly
  6. 6.Division of Cardiovascular Epidemiology, Institute of Environmental MedicineKarolinska InstitutetStockholmSweden
  7. 7.Institute of Public Health and Clinical NutritionUniversity of Eastern FinlandKuopioFinland
  8. 8.Foundation for Research in Health, Exercise and NutritionKuopio Research Institute of Exercise MedicineKuopioFinland
  9. 9.Department of MedicineUniversity Medical Center GroningenGroningenThe Netherlands
  10. 10.Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Clinical and Experimental MedicineUniversity of PerugiaPerugiaItaly
  11. 11.Assistance Publique–Hôpitaux de Paris; Service Endocrinologie–Metabolisme, Groupe Hôpitalier Pitie-SalpetriereUnités de Prévention CardiovasculaireParisFrance
  12. 12.Centre for Cardiovascular GeneticsUniversity College LondonLondonUK

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