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

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Abstract

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.

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Figure 1: Genomic location of detectable CMEs.

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References

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  5. Curtis, R., Geesaman, B.J. & DiStefano, P.S. Ageing and metabolism: drug discovery opportunities. Nat. Rev. Drug Discov. 4, 569–580 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Castillo, J.J. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Youssoufian, H. & Pyeritz, R.E. Mechanisms and consequences of somatic mosaicism in humans. Nat. Rev. Genet. 3, 748–758 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Dumanski, J.P. & Piotrowski, A. Structural genetic variation in the context of somatic mosaicism. Methods Mol. Biol. 838, 249–272 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Martin, L.J. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Balkau, B. 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).

    CAS  PubMed  Google Scholar 

  19. Meyre, D. 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).

    Article  CAS  PubMed  Google Scholar 

  20. Murphy, N. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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).

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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.

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Correspondence to Philippe Froguel.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4 and Supplementary Table 1 (PDF 4201 kb)

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Bonnefond, A., Skrobek, B., Lobbens, S. et al. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nat Genet 45, 1040–1043 (2013). https://doi.org/10.1038/ng.2700

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