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DCAF4, a novel gene associated with leucocyte telomere length.
Friday,2015-08-28 11:59 America/Los_Angeles — zdrager
| Title | DCAF4, a novel gene associated with leucocyte telomere length. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Mangino, M, Christiansen, L, Stone, R, Hunt, SC, Horvath, K, Eisenberg, DTA, Kimura, M, Petersen, I, Kark, JD, Herbig, U, Reiner, AP, Benetos, A, Codd, V, Nyholt, DR, Sinnreich, R, Christensen, K, Nassar, H, Hwang, S-J, Levy, D, Bataille, V, Fitzpatrick, AL, Chen, W, Berenson, GS, Samani, NJ, Martin, NG, Tishkoff, S, Schork, NJ, Kyvik, KO, Dalgård, C, Spector, TD, Aviv, A |
| Journal | J Med Genet |
| Volume | 52 |
| Issue | 3 |
| Pagination | 157-62 |
| Date Published | 2015 Mar |
| ISSN | 1468-6244 |
| Keywords | Alleles, Carrier Proteins, Gene Expression Regulation, Genome-Wide Association Study, Humans, Leukocytes, Melanoma, Risk Factors, Telomere, Telomere Homeostasis |
| Abstract | <p><b>BACKGROUND: </b>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).</p><p><b>RESULTS: </b>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).</p><p><b>CONCLUSIONS: </b>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.</p> |
| DOI | 10.1136/jmedgenet-2014-102681 |
| Alternate Journal | J. Med. Genet. |
| PubMed ID | 25624462 |
| PubMed Central ID | PMC4345921 |
| Grant List | 2R01AG016592 / AG / NIA NIH HHS / United States 5R01ES021724 / ES / NIEHS NIH HHS / United States AG023629 / AG / NIA NIH HHS / United States HHSN268200800007C / / PHS HHS / United States HHSN268201200036C / / PHS HHS / United States HL055673 / HL / NHLBI NIH HHS / United States HL080295 / HL / NHLBI NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States HL54471 / HL / NHLBI NIH HHS / United States HL54472 / HL / NHLBI NIH HHS / United States HL54473 / HL / NHLBI NIH HHS / United States HL54495 / HL / NHLBI NIH HHS / United States HL54496 / HL / NHLBI NIH HHS / United States HL54509 / HL / NHLBI NIH HHS / United States HL54515 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States N01HC55222 / HC / NHLBI NIH HHS / United States N01HC85079 / HC / NHLBI NIH HHS / United States N01HC85080 / HC / NHLBI NIH HHS / United States N01HC85081 / HC / NHLBI NIH HHS / United States N01HC85082 / HC / NHLBI NIH HHS / United States N01HC85083 / HC / NHLBI NIH HHS / United States N01HC85086 / HC / NHLBI NIH HHS / United States R01 AG016592 / AG / NIA NIH HHS / United States R01 HL116446 / HL / NHLBI NIH HHS / United States R01AG030678 / AG / NIA NIH HHS / United States R01AG20132 / AG / NIA NIH HHS / United States R01AG21593 / AG / NIA NIH HHS / United States R24 HD042828 / HD / NICHD NIH HHS / United States / / British Heart Foundation / United Kingdom / / Intramural NIH HHS / United States / / Wellcome Trust / United Kingdom |