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Diabetologia

, 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
Article

Abstract

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusions/interpretation

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.

Keywords

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

Abbreviations

1,25(OH)D

1,25-Dihydroxyvitamin D

25(OH)D

25-Hydroxyvitamin D

ASAP

Advanced Study of Aortic Pathology

Bifmax

Maximum intima–media thickness of the bifurcation

Bifmean

Mean intima–media thickness of the bifurcation

CCmax

Maximum intima–media thickness of the common carotid artery

CCmean

Mean intima–media thickness of the common carotid artery

cIMT

Carotid intima–media thickness

CRP

C-reactive protein

CVD

Cardiovascular disease

IMPROVE

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

IMTmax

Maximum intima–media thickness of the entire carotid tree

IMTmean

Mean intima–media thickness of the entire carotid tree

IMTmean-max

Mean of the IMTmax

SNPs

Single nucleotide polymorphisms

VDR

Vitamin D receptor

Notes

Funding

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.

Contribution

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

125_2014_3215_MOESM1_ESM.pdf (12 kb)
ESM Table 1 (PDF 11 kb)
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ESM Table 2 (PDF 18 kb)
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ESM Table 3 (PDF 158 kb)
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ESM Table 6 (PDF 86 kb)
125_2014_3215_MOESM7_ESM.pdf (88 kb)
ESM Table 7 (PDF 87 kb)

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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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