|
|
| PMID |
|
|
| TITLE |
|
| DCAF4, a novel gene associated with leucocyte telomere length. |
|
| ABSTRACT |
|
| BACKGROUND |
NlmCategory: 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 |
NlmCategory: 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 |
NlmCategory: 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. |
| Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| aheadofprint |
2015/01/26 |
| entrez |
2015/01/28 06:00 |
| pubmed |
2015/01/28 06:00 |
| medline |
2016/03/02 06:00 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Mangino M |
|
Mangino |
Massimo |
M |
|
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK. |
| Christiansen L |
|
Christiansen |
Lene |
L |
|
Epidemiology Unit, The Danish Aging Research Center and The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark Department of Clinical Genetics, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. |
| Stone R |
|
Stone |
Rivka |
R |
|
Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA. |
| Hunt SC |
|
Hunt |
Steven C |
SC |
|
Cardiovascular Genetics Division, Department of Medicine, University of Utah, Salt Lake City, Utah, USA. |
| Horvath K |
|
Horvath |
Kent |
K |
|
Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA. |
| Eisenberg DT |
|
Eisenberg |
Dan T A |
DT |
|
Department of Anthropology, University of Washington, Seattle, Washington, USA Center for Studies in Demography and Ecology, University of Washington, Seattle, Washington, USA. |
| Kimura M |
|
Kimura |
Masayuki |
M |
|
Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA. |
| Petersen I |
|
Petersen |
Inge |
I |
|
Epidemiology Unit, The Danish Aging Research Center and The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark. |
| Kark JD |
|
Kark |
Jeremy D |
JD |
|
Epidemiology Unit, Hebrew University-Hadassah School of Public Health and Community Medicine, Jerusalem, Israel. |
| Herbig U |
|
Herbig |
Utz |
U |
|
Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA. |
| Reiner AP |
|
Reiner |
Alex P |
AP |
|
Department of Epidemiology, University of Washington, Seattle, Washington, USA Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. |
| Benetos A |
|
Benetos |
Athanase |
A |
|
Department of Geriatrics, Universite de Lorraine INSERM U961, Nancy, France. |
| Codd V |
|
Codd |
Veryan |
V |
|
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK. |
| Nyholt DR |
|
Nyholt |
Dale R |
DR |
|
QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Sinnreich R |
|
Sinnreich |
Ronit |
R |
|
Epidemiology Unit, Hebrew University-Hadassah School of Public Health and Community Medicine, Jerusalem, Israel. |
| Christensen K |
|
Christensen |
Kaare |
K |
|
Epidemiology Unit, The Danish Aging Research Center and The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark Department of Clinical Genetics, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. |
| Nassar H |
|
Nassar |
Hisham |
H |
|
Department of Cardiology, Hadassah University Medical Center, Jerusalem, Israel. |
| Hwang SJ |
|
Hwang |
Shih-Jen |
SJ |
|
Population Sciences Branch of the National Heart, Lung and Blood Institute, Bethesda, Maryland, USA The Framingham Heart Study, Framingham, Massachusetts, USA. |
| Levy D |
|
Levy |
Daniel |
D |
|
Population Sciences Branch of the National Heart, Lung and Blood Institute, Bethesda, Maryland, USA The Framingham Heart Study, Framingham, Massachusetts, USA. |
| Bataille V |
|
Bataille |
Veronique |
V |
|
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK Department of Dermatology, West Herts NHS Trust, Herts, UK. |
| Fitzpatrick AL |
|
Fitzpatrick |
Annette L |
AL |
|
Department of Epidemiology, University of Washington, Seattle, Washington, USA. |
| Chen W |
|
Chen |
Wei |
W |
|
Center for Cardiovascular Health, Tulane University, New Orleans, Louisiana, USA. |
| Berenson GS |
|
Berenson |
Gerald S |
GS |
|
Center for Cardiovascular Health, Tulane University, New Orleans, Louisiana, USA. |
| Samani NJ |
|
Samani |
Nilesh J |
NJ |
|
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Tishkoff S |
|
Tishkoff |
Sarah |
S |
|
Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA. |
| Schork NJ |
|
Schork |
Nicholas J |
NJ |
|
Department of Molecular and Experimental Medicine, The Scripps Research Institute, San Diego, California, USA. |
| Kyvik KO |
|
Kyvik |
Kirsten Ohm |
KO |
|
Epidemiology Unit, The Danish Aging Research Center and The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark. |
| Dalgård C |
|
Dalgård |
Christine |
C |
|
Institute of Public Health, Environmental Medicine, University of Southern Denmark, Odense, Denmark. |
| Spector TD |
|
Spector |
Timothy D |
TD |
|
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. |
| Aviv A |
|
Aviv |
Abraham |
A |
|
Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA. |
|
| INVESTIGATORS |
|
|
| JOURNAL |
|
| VOLUME: 52 |
| ISSUE: 3 |
| TITLE: Journal of medical genetics |
| ISOABBREVIATION: J. Med. Genet. |
| YEAR: 2015 |
| MONTH: Mar |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1468-6244 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: J Med Genet |
| COUNTRY: England |
| ISSNLINKING: 0022-2593 |
| NLMUNIQUEID: 2985087R |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Meta-Analysis |
| Research Support, N.I.H., Extramural |
| Research Support, N.I.H., Intramural |
| Research Support, Non-U.S. Gov't |
|
| COMMENTS AND CORRECTIONS |
|
| REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
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|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| 2R01AG016592 |
NIA NIH HHS |
United States |
| 5R01ES021724 |
NIEHS NIH HHS |
United States |
| AG023629 |
NIA NIH HHS |
United States |
| HHSN268200800007C |
PHS HHS |
United States |
| HHSN268201200036C |
PHS HHS |
United States |
| HL055673 |
NHLBI NIH HHS |
United States |
| HL080295 |
NHLBI NIH HHS |
United States |
| HL087652 |
NHLBI NIH HHS |
United States |
| HL105756 |
NHLBI NIH HHS |
United States |
| HL54471 |
NHLBI NIH HHS |
United States |
| HL54472 |
NHLBI NIH HHS |
United States |
| HL54473 |
NHLBI NIH HHS |
United States |
| HL54495 |
NHLBI NIH HHS |
United States |
| HL54496 |
NHLBI NIH HHS |
United States |
| HL54509 |
NHLBI NIH HHS |
United States |
| HL54515 |
NHLBI NIH HHS |
United States |
| N01-HC-25195 |
NHLBI NIH HHS |
United States |
| N01HC55222 |
NHLBI NIH HHS |
United States |
| N01HC85079 |
NHLBI NIH HHS |
United States |
| N01HC85080 |
NHLBI NIH HHS |
United States |
| N01HC85081 |
NHLBI NIH HHS |
United States |
| N01HC85082 |
NHLBI NIH HHS |
United States |
| N01HC85083 |
NHLBI NIH HHS |
United States |
| N01HC85086 |
NHLBI NIH HHS |
United States |
| R01 AG016592 |
NIA NIH HHS |
United States |
| R01 HL116446 |
NHLBI NIH HHS |
United States |
| R01AG030678 |
NIA NIH HHS |
United States |
| R01AG20132 |
NIA NIH HHS |
United States |
| R01AG21593 |
NIA NIH HHS |
United States |
| R24 HD042828 |
NICHD NIH HHS |
United States |
|
British Heart Foundation |
United Kingdom |
|
Intramural NIH HHS |
United States |
|
Wellcome Trust |
United Kingdom |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
| KEYWORD |
| Complex traits |
| Telomere |
| cancer: skin |
| melanoma |
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Alleles |
|
| Carrier Proteins |
genetics |
| Gene Expression Regulation |
genetics |
| Genome-Wide Association Study |
genetics |
| Humans |
genetics |
| Leukocytes |
cytology |
| Melanoma |
pathology |
| Risk Factors |
pathology |
| Telomere |
genetics |
| Telomere Homeostasis |
genetics |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| 0 |
Carrier Proteins |
| 0 |
WDR21A protein, human |
|
| OTHER ID's |
|
| OTHERID |
SOURCE |
| PMC4345921 |
NLM |
|
|
