DCAF4, a novel gene associated with leucocyte telomere length

J Med Genet. 2015 Mar;52(3):157-62. doi: 10.1136/jmedgenet-2014-102681. Epub 2015 Jan 26.

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.

Keywords: Complex traits; Telomere; cancer: skin; melanoma.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / blood
  • Carrier Proteins / genetics*
  • Gene Expression Regulation
  • Genome-Wide Association Study
  • Humans
  • Leukocytes / cytology*
  • Melanoma / blood
  • Melanoma / genetics*
  • Melanoma / pathology
  • Risk Factors
  • Telomere / genetics
  • Telomere Homeostasis / genetics*

Substances

  • Carrier Proteins
  • DCAF4 protein, human

Grant support