TY - JOUR T1 - DCAF4, a novel gene associated with leucocyte telomere length. JF - J Med Genet Y1 - 2015 A1 - Mangino, Massimo A1 - Christiansen, Lene A1 - Stone, Rivka A1 - Hunt, Steven C A1 - Horvath, Kent A1 - Eisenberg, Dan T A A1 - Kimura, Masayuki A1 - Petersen, Inge A1 - Kark, Jeremy D A1 - Herbig, Utz A1 - Reiner, Alex P A1 - Benetos, Athanase A1 - Codd, Veryan A1 - Nyholt, Dale R A1 - Sinnreich, Ronit A1 - Christensen, Kaare A1 - Nassar, Hisham A1 - Hwang, Shih-Jen A1 - Levy, Daniel A1 - Bataille, Veronique A1 - Fitzpatrick, Annette L A1 - Chen, Wei A1 - Berenson, Gerald S A1 - Samani, Nilesh J A1 - Martin, Nicholas G A1 - Tishkoff, Sarah A1 - Schork, Nicholas J A1 - Kyvik, Kirsten Ohm A1 - Dalgård, Christine A1 - Spector, Timothy D A1 - Aviv, Abraham KW - Alleles KW - Carrier Proteins KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Humans KW - Leukocytes KW - Melanoma KW - Risk Factors KW - Telomere KW - Telomere Homeostasis AB -

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.

VL - 52 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25624462?dopt=Abstract ER - TY - JOUR T1 - Telomeres and the natural lifespan limit in humans. JF - Aging (Albany NY) Y1 - 2017 A1 - Steenstrup, Troels A1 - Kark, Jeremy D A1 - Verhulst, Simon A1 - Thinggaard, Mikael A1 - Hjelmborg, Jacob V B A1 - Dalgård, Christine A1 - Kyvik, Kirsten Ohm A1 - Christiansen, Lene A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Petersen, Inge A1 - Kimura, Masayuki A1 - Benetos, Athanase A1 - Labat, Carlos A1 - Sinnreich, Ronit A1 - Hwang, Shih-Jen A1 - Levy, Daniel A1 - Hunt, Steven C A1 - Fitzpatrick, Annette L A1 - Chen, Wei A1 - Berenson, Gerald S A1 - Barbieri, Michelangela A1 - Paolisso, Giuseppe A1 - Gadalla, Shahinaz M A1 - Savage, Sharon A A1 - Christensen, Kaare A1 - Yashin, Anatoliy I A1 - Arbeev, Konstantin G A1 - Aviv, Abraham AB -

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.

VL - 9 IS - 4 ER -