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Osteoporosis International

, Volume 27, Issue 6, pp 2065–2075 | Cite as

Quantitative genetics of circulating Dickkopf-related protein 1 (DKK1) in community-based sample of UK twins

  • J. Prakash
  • F. M. K. Williams
  • S. Trofimov
  • G. Surdulescu
  • T. Spector
  • G. Livshits
Original Article

Abstract

Summary

Dickkopf-related protein 1 (DKK1) is a major inhibitor of Wnt signalling pathway but also plays an important role in bone formation. Its circulating levels appear to correlate significantly with plasma levels of inflammatory factors, fractalkine and IL-6. This study, using a large sample of UK twins, showed that the variation of each of these factors and correlation between them was explained by the genetic factors, and indicated possible association with DKK1 gene variants.

Introduction

DKK1 is involved in the development of several inflammatory conditions related to bone and joint degradation. Our objectives were to explore the genetic contribution (heritability) to circulating DKK1 variation and its correlation with other inflammatory cytokines, interleukin 6 (IL-6) and fractalkine, and to test whether the DKK1 heritability could be attributable to single nucleotide polymorphisms (SNPs) mapped to DKK1, IL-6 and FRCT genes.

Methods

The study included a large community-based sample of 4939 women drawn from the general UK population. Plasma samples were analysed for circulating levels of DKK1, IL-6 and fractalkine (FRCT); 65 SNPs of DKK1, IL-6 and FRCT candidate genes, with MAF >0.1, were examined. We applied variance component analysis to evaluate contribution of putative genetic (including above SNPs) and environmental factors to variation of DKK1, and its correlation with IL-6 and FRCT.

Results

Putative genetic factors explained 42.2 ± 2 % of the total variation of circulating DKK1 levels, and were also significant for fractalkine and IL-6 variations. Most importantly, we report significant phenotypic (0.208 ± 0.006–0.459 ± 0.007) and genetic (0.338 ± 0.069–0.617 ± 0.033) correlations between these molecules. We found evidence suggestive of association between the DKK1 and its structural genes variants.

Conclusions

Circulating DKK1 levels correlated significantly with levels of IL-6 and FRCT, known risk factors for several inflammatory processes suggesting a potential role of DKK1 in inflammation and tissue injury. Our results suggest the contribution of genetic factors in inter-individual variation of DKK1 levels in human population. However, further studies are required to determine genetic polymorphisms affecting DKK1 variation and its correlation with IL-6 and FRCT.

Keywords

DKK1 Fractalkine Genetic analysis Heritability Interleukin-6 SNP 

Abbreviations

APO_A1

Apo lipoprotein A1, g/l

APO_B

Apo lipoprotein B, g/l

BMD-T

Bone mineral density total, kg

BMI

Body mass index, kg/m2

CVD

Cardiovascular disease

DKK1

Dickkopf-related protein 1

DM

Diabetes mellitus

DZ

Dizygotic twin

ELISA

Enzyme-linked immunosorbent assay

FBM

Fat body mass, kg/m2

FRCT

Fractalkine, pg/ml

HDL

High-density lipoprotein, mmol/l

IL-6

Interleukin 6, pg/ml

LBM

Lean body mass, kg/m2

LDL

Low-density lipoprotein, mmol/l

LRP

Lipoprotein-related receptor

MZ

Monozygotic twin

TG

Triglycerides mmol/l

VAD

Variance attributable to additive genetic effects

VEN

Variance attributable to random environmental effects

VTW

Variance attributable to environmental effects shared by twins

Notes

Acknowledgments

The present study was supported by the Israel Science Foundation (grant number #1018/13) to GL. FW is supported by Arthritis Research UK.

TwinsUK. The study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR.

Compliance with ethical standards

Conflicts of interest

None

Supplementary material

198_2016_3486_MOESM1_ESM.doc (512 kb)
ESM 1 (DOC 512 kb)

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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2016

Authors and Affiliations

  • J. Prakash
    • 1
  • F. M. K. Williams
    • 2
  • S. Trofimov
    • 1
  • G. Surdulescu
    • 2
  • T. Spector
    • 2
  • G. Livshits
    • 1
    • 2
    • 3
  1. 1.Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  2. 2.Department of Twin Research and Genetic EpidemiologyKing’s College LondonStrandUK
  3. 3.Lilian and Marcel Pollak Chair of Biological Anthropology, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael

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