DCAF4 , a novel gene associated with leucocyte telomere length

Massimo Mangino (1) , Dan Christiansen (2, 3, 4) , Rivka Stone (5) , Steven Hunt (6) , Kent Horvath (5) , Dan Eisenberg (7, 8) , Masayuki Kimura (9) , Inge Petersen (2, 3) , Jeremy Kark (10) , Utz Herbig (5) , Alex Reiner (11, 7) , Athanase Benetos (12, 13) , Veryan Codd (14, 15) , Dale Nyholt (16) , Ronit Sinnreich (10) , Kaare Christensen (2, 3, 4) , Hisham Nassar (17) , Shih-Jen Hwang (18) , Daniel Levy (18) , Veronique Bataille (1) , Annette Fitzpatrick (11) , Wei Chen (19) , Gerald Berenson (19) , Nilesh Samani (20) , Nicholas Martin (16) , Sarah Tishkoff (21) , Nicholas J. Schork (22) , Kirsten Ohm Kyvik (23, 2, 3, 24) , Christine Dalgård (25) , Timothy D. Spector (1) , Abraham Aviv (9)

1 King‘s College London
2 The Danish Aging Research Center, Epidemiology, Institute of Public Health
3 The Danish Twin Registry
4 Department of Clinical Biochemistry and Pharmacology; OdenseUniversity Hospital; Sdr. Boulevard 29
5 NJMS - Rutgers New Jersey Medical School
6 School of Medicine [University of Utah, Salt Lake City]
7 Center for Studies in Demography and Ecology
8 WSU - Washington State University
9 Center of Human Development and Aging, New Jersey Medical School
10 Hadassah School of Public Health and Community Medicine
11 Department of Epidemiology, University of Washington
12 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique
13 Service de Gériatrie [CHRU Nancy]
14 Department of Cardiovascular Sciences [Leicester]
15 National Institute for Health Research (NIHR)
16 QIMR Berghofer Medical Research Institute
17 Hadassah Hebrew University Medical Center [Jerusalem]
18 NHLBI - National Heart, Lung, and Blood Institute [Bethesda]
19 Tulane Center for Cardiovascular Health
20 Leicester NIHR Biomedical Research Unit in Cardiovascular Disease
21 University of Pennsylvania
22 Department of Molecular Medicine [Scripps Research Institute]
23 Institute of Regional Health Services Research
24 OPEN - Odense Patient Data Explorative Network
25 SDU - University of Southern Denmark

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.

Mots clés: Complex traits; Telomere; cancer: skin; melanoma

Domaines: Cardiologie et système cardiovasculaire

Massimo Mangino, Dan Christiansen, Rivka Stone, Steven Hunt, Kent Horvath, et al.. DCAF4 , a novel gene associated with leucocyte telomere length. Journal of Medical Genetics, 2015, 52 (3), pp.157 - 162. ⟨10.1136/jmedgenet-2014-102681⟩. ⟨hal-01743522⟩