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Original article
DCAF4, a novel gene associated with leucocyte telomere length
  1. Massimo Mangino1,2,
  2. Lene Christiansen3,4,
  3. Rivka Stone5,
  4. Steven C Hunt6,
  5. Kent Horvath5,
  6. Dan T A Eisenberg7,8,
  7. Masayuki Kimura5,
  8. Inge Petersen3,
  9. Jeremy D Kark9,
  10. Utz Herbig5,
  11. Alex P Reiner10,11,
  12. Athanase Benetos12,
  13. Veryan Codd13,14,
  14. Dale R Nyholt15,
  15. Ronit Sinnreich9,
  16. Kaare Christensen3,4,
  17. Hisham Nassar16,
  18. Shih-Jen Hwang17,18,
  19. Daniel Levy17,18,
  20. Veronique Bataille1,19,
  21. Annette L Fitzpatrick10,
  22. Wei Chen20,
  23. Gerald S Berenson20,
  24. Nilesh J Samani13,14,
  25. Nicholas G Martin15,
  26. Sarah Tishkoff21,
  27. Nicholas J Schork22,
  28. Kirsten Ohm Kyvik3,23,24,
  29. Christine Dalgård25,
  30. Timothy D Spector1,
  31. Abraham Aviv5
  1. 1Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
  2. 2National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas’ Foundation Trust, London, UK
  3. 3Epidemiology Unit, The Danish Aging Research Center and The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark
  4. 4Department of Clinical Genetics, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
  5. 5Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA
  6. 6Cardiovascular Genetics Division, Department of Medicine, University of Utah, Salt Lake City, Utah, USA
  7. 7Department of Anthropology, University of Washington, Seattle, Washington, USA
  8. 8Center for Studies in Demography and Ecology, University of Washington, Seattle, Washington, USA
  9. 9Epidemiology Unit, Hebrew University-Hadassah School of Public Health and Community Medicine, Jerusalem, Israel
  10. 10Department of Epidemiology, University of Washington, Seattle, Washington, USA
  11. 11Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  12. 12Department of Geriatrics, Universite de Lorraine INSERM U961, Nancy, France
  13. 13Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
  14. 14National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
  15. 15QIMR Berghofer Medical Research Institute, Brisbane, Australia
  16. 16Department of Cardiology, Hadassah University Medical Center, Jerusalem, Israel
  17. 17Population Sciences Branch of the National Heart, Lung and Blood Institute, Bethesda, Maryland, USA
  18. 18The Framingham Heart Study, Framingham, Massachusetts, USA
  19. 19Department of Dermatology, West Herts NHS Trust, Herts, UK
  20. 20Center for Cardiovascular Health, Tulane University, New Orleans, Louisiana, USA
  21. 21Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  22. 22Department of Molecular and Experimental Medicine, The Scripps Research Institute, San Diego, California, USA
  23. 23Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark
  24. 24Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark
  25. 25Institute of Public Health, Environmental Medicine, University of Southern Denmark, Odense, Denmark
  1. Correspondence to Dr Abraham Aviv, The Center of Human Development and Aging, New Jersey Medical School, UMDNJ, Newark, NJ 07103; avivab@umdnj.edu Massimo Mangino, King's College London, Department of Twin Research & Genetic Epidemiology, St. Thomas’ Hospital Campus, South Wing, Block D, 3rd Floor, Westminster Bridge Road, London SE1 7EH, UK; massimo.mangino{at}kcl.ac.uk

Abstract

Background Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).

Results Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10−10) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10−3 and 2×10−3, respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10−169 to 3.42×10−24.

Conclusions We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

  • Complex traits
  • Telomere
  • cancer: skin
  • melanoma

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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