期刊
JOURNAL OF MEDICAL GENETICS
卷 52, 期 3, 页码 157-162出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2014-102681
关键词
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资金
- Wellcome Trust [076113/C/04/Z]
- European Community's Seventh Framework Programme (FP7)
- National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- King's College London
- ERC Advanced Principal Investigator award
- National Institute of Environmental Health Science [5R01ES021724]
- National Institute on Aging [2R01AG016592]
- NIH [N01-HC-25195, R01AG20132, R01AG21593, R01AG030678]
- National Heart, Lung, and Blood Institute
- Center for Population Studies of the NHLBI
- NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756]
- National Institute on Aging (NIA) [AG023629]
- British Heart Foundation (BHF)
- BHF
- NIHR Leicester Cardiovascular Biomedical Research Unit
- NIHR Senior Investigator award
- US-Israel Binational Science Foundation
- Israel Science Foundation
- US-AID Program for Middle Eastern Regional Cooperation
- French Fondation pour la Recherche Medicale [FRM DCV2007-0409250]
- Plan Pluriformation [PPF815 PSVT-2005]
- Australian Research Council [A7960034, A79906588, A79801419, DP0212016, DP0343921]
- European Community
- ENGAGE project [HEALTH-F4-2007-201413]
- National Health and Medical Research Council (NHMRC)-European Union Collaborative Research Grant [496739]
- NHMRC Fellowship [619667]
- ARC Future Fellowship [FT0991022, FT110100548]
- NHMRC (Medical Bioinformatics Genomics Proteomics Program) [389891]
- Netherlands Scientific Organisation [NWO 480-05-003]
- NIHR programme grant [RP-PG-0310-1002]
- [HL54471]
- [HL54472]
- [HL54473]
- [HL54495]
- [HL54496]
- [HL54509]
- [HL54515]
- [HL055673]
- National Institute for Health Research [NF-SI-0514-10027, NF-SI-0611-10170] Funding Source: researchfish
- Australian Research Council [FT110100548] Funding Source: Australian Research Council
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= 6.4x10(-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= 4.1x10(-3) and 2x10(-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 1.97x10(-169) to 3.42x10(-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.
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