Letter | Published:

Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications

Nature Genetics volume 45, pages 10401043 (2013) | Download Citation



Large chromosomal clonal mosaic events (CMEs) have been suggested to be linked to aging1,2,3 and to predict cancer2,3. Type 2 diabetes (T2D) has been conceptualized as an accelerated-aging disease4,5,6 and is associated with higher prevalence of cancers7,8,9,10,11. Here we aimed to assess the association between T2D and CME occurrence in blood. We evaluated the presence of CMEs in 7,659 individuals (including 2,208 with T2D) using DNA arrays. A significant association between CME occurrence and T2D was found (odds ratio (OR) = 5.3; P = 5.1 × 10−5) and was stronger when we only considered non-obese individuals with T2D (OR = 5.6; P = 4.9 × 10−5). Notably, CME carriers with T2D had higher prevalence of vascular complications than non-carriers with T2D (71.4% versus 37.1%, respectively; P = 7.7 × 10−4). In CME carriers, we found an increase in the percentage of abnormal cells over 6 years (P = 8.60 × 10−3). In conclusion, given the increased risk of cancer in CME carriers2,3, our results may have profound clinical implications in patients with severe T2D.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. Age-related somatic structural changes in the nuclear genome of human blood cells. Am. J. Hum. Genet. 90, 217–228 (2012).

  2. 2.

    et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44, 651–658 (2012).

  3. 3.

    et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 44, 642–650 (2012).

  4. 4.

    Diabetes and aging: epidemiologic overview. Clin. Geriatr. Med. 24, 395–405 (2008).

  5. 5.

    , & Ageing and metabolism: drug discovery opportunities. Nat. Rev. Drug Discov. 4, 569–580 (2005).

  6. 6.

    Genetics of aging: implications for drug discovery and development. Am. J. Clin. Nutr. 83, 466S–469S (2006).

  7. 7.

    et al. Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults. Diabetes Care 35, 835–844 (2012).

  8. 8.

    & Obesity, type 2 diabetes and cancer: the insulin and insulin-like growth factor connection. Endocr. Relat. Cancer 19, F27–F45 (2012).

  9. 9.

    et al. Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologia 55, 1607–1618 (2012).

  10. 10.

    et al. Diabetes and cancer (2): evaluating the impact of diabetes on mortality in patients with cancer. Diabetologia 55, 1619–1632 (2012).

  11. 11.

    et al. Increased incidence of non-Hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: a meta-analysis of observational studies. Blood 119, 4845–4850 (2012).

  12. 12.

    & Mechanisms and consequences of somatic mosaicism in humans. Nat. Rev. Genet. 3, 748–758 (2002).

  13. 13.

    & Structural genetic variation in the context of somatic mosaicism. Methods Mol. Biol. 838, 249–272 (2012).

  14. 14.

    et al. Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8, 460–472 (2009).

  15. 15.

    et al. The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet. 8, e1002793 (2012).

  16. 16.

    et al. A quantitative trait locus influencing type 2 diabetes susceptibility maps to a region on 5q in an extended French family. Diabetes 51, 3568–3572 (2002).

  17. 17.

    et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).

  18. 18.

    An epidemiologic survey from a network of French Health Examination Centres, (D.E.S.I.R.): epidemiologic data on the insulin resistance syndrome. Rev. Epidemiol. Sante Publique 44, 373–375 (1996).

  19. 19.

    et al. A genome-wide scan for childhood obesity–associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2. Diabetes 53, 803–811 (2004).

  20. 20.

    et al. Dietary fibre intake and risks of cancers of the colon and rectum in the European prospective investigation into cancer and nutrition (EPIC). PLoS ONE 7, e39361 (2012).

  21. 21.

    ADA. Diabetes care standards, guidelines, and related documents. Diabetes Care 32 (suppl. 1), S1–S2 (2009).

  22. 22.

    et al. Normalization of Illumina Infinium whole-genome SNP data improves copy number estimates and allelic intensity ratios. BMC Bioinformatics 9, 409 (2008).

  23. 23.

    et al. Adjustment of genomic waves in signal intensities from whole-genome SNP genotyping platforms. Nucleic Acids Res. 36, e126 (2008).

  24. 24.

    et al. High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping. Genome Res. 16, 1136–1148 (2006).

  25. 25.

    et al. Mosaic uniparental disomies and aneuploidies as large structural variants of the human genome. Am. J. Hum. Genet. 87, 129–138 (2010).

Download references


We are sincerely indebted to all participants in the genetic study. We thank M. Deweirder and F. Allegaert for their technical assistance and their invaluable management of DNA samples. This study was supported by the Contrat de Projets Etat–Région Nord-Pas-De-Calais (CPER Axe Cardio-Diabète to P.F.), the Délégation Régionale à la Recherche et à la Technologie de la Région Nord-Pas-De-Calais (DRRT), the European Union (Fonds Européen de Développement Régional (FEDER)) and the Centre National de la Recherche Scientifique (CNRS).

Author information

Author notes

    • Boris Skrobek
    •  & Stéphane Lobbens

    These authors contributed equally to this work.


  1. Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8199, Lille Pasteur Institute, Lille, France.

    • Amélie Bonnefond
    • , Boris Skrobek
    • , Stéphane Lobbens
    • , Elodie Eury
    • , Dorothée Thuillier
    • , Stéphane Cauchi
    • , Loïc Yengo
    •  & Philippe Froguel
  2. Lille II University, Lille, France.

    • Amélie Bonnefond
    • , Boris Skrobek
    • , Stéphane Lobbens
    • , Elodie Eury
    • , Dorothée Thuillier
    • , Stéphane Cauchi
    • , Loïc Yengo
    •  & Philippe Froguel
  3. European Genomic Institute for Diabetes (EGID), Lille, France.

    • Amélie Bonnefond
    • , Boris Skrobek
    • , Stéphane Lobbens
    • , Elodie Eury
    • , Dorothée Thuillier
    • , Stéphane Cauchi
    • , Loïc Yengo
    •  & Philippe Froguel
  4. Institut Inter-Régional pour la Santé (IRSA), La Riche, France.

    • Olivier Lantieri
  5. Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Centre for Research in Epidemiology and Population Health, Villejuif, France.

    • Beverley Balkau
  6. University Paris–Sud, Villejuif, France.

    • Beverley Balkau
  7. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • Elio Riboli
  8. Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.

    • Michel Marre
  9. INSERM U695, Paris 7 University, Paris, France.

    • Michel Marre
  10. Department of Endocrinology and Diabetology, Corbeil-Essonnes Hospital, Essonnes, France.

    • Guillaume Charpentier
  11. Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.

    • Philippe Froguel
  12. Qatar Biomedical Research Institute (QBRI), Doha, Qatar.

    • Philippe Froguel


  1. Search for Amélie Bonnefond in:

  2. Search for Boris Skrobek in:

  3. Search for Stéphane Lobbens in:

  4. Search for Elodie Eury in:

  5. Search for Dorothée Thuillier in:

  6. Search for Stéphane Cauchi in:

  7. Search for Olivier Lantieri in:

  8. Search for Beverley Balkau in:

  9. Search for Elio Riboli in:

  10. Search for Michel Marre in:

  11. Search for Guillaume Charpentier in:

  12. Search for Loïc Yengo in:

  13. Search for Philippe Froguel in:


A.B. and P.F. designed the study and wrote the manuscript. B.S. and L.Y. performed the statistical analyses (CME detection and association analyses) and contributed to writing the manuscript. A.B. contributed to the statistical analyses. S.L. and E.E. performed the genotyping. D.T. contributed to the genotyping. S.C., O.L., B.B., E.R., M.M., G.C. and P.F. contributed to cohort study samples and researched data. All authors approved and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Philippe Froguel.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4 and Supplementary Table 1

About this article

Publication history






Further reading