Grant Details
Grant Number: |
2R01CA065725-11A1 Interpret this number |
Primary Investigator: |
Hunter, David |
Organization: |
Brigham And Women'S Hospital |
Project Title: |
Cohort Study of Genetic Susceptibility to Breast Cancer |
Fiscal Year: |
2007 |
Abstract
DESCRIPTION (provided by applicant): We propose to continue our study of the environmental and inherited determinants of breast cancer in women. Telomere length, measured in peripheral blood white cells, has emerged as a biomarker of ageing, and cancer risk. Telomeres are TTAGGG repeat complexes at the end of chromosomes, that protect against degradation, fusion, and aberrant recombination of chromosomes. As telomeres shorten with each cell replication cycle, they are an indicator of the number of cell divisions a cell has undergone. Shorter telomere length has been associated with risks of head and neck, lung, renal cell and bladder cancers, however, no studies of breast cancer have been published, although telomere length has been shown to shorten in normal breast tissue in older women. Twin studies have shown that telomere length has a substantial heritable component, however, no genetic variants have been linked to telomere length. We propose to (i) Establish whether telomere length in peripheral white blood cells is a predictor of breast cancer risk in premenopausal and postmenopausal breast cancer from the Nurses' Health Studies I and II, and postmenopausal women from the Women's Health Study; (ii) use a multistage design starting with a completed whole genome SNP scan among 2400 postmenopausal women in NHS I to locate the inherited genetic variants associated with rate of telomere shortening; and (iii) examine the environmental and lifestyle predictors of telomere length. Among the novel aspects of this project is that it will be one of the first to apply dense data from a whole genome SNP scan to a continuous quantitative outcome. This project will integrate the genetic and environmental determinants of telomere length for the first time, and should give insight into the biological and modifiable causes of age-related cancers. Telomeres are repeated nucleotide sequences that protect the ends of our chromosomes from degradation. They get shortened during a cell's life and thus represent a marker of aging. We will examine whether shorter telomeres in white blood cells are a marker of a woman's risk of breast cancer, and seek the genetic and lifestyle determinants of shorter telomeres. Understanding the causes of the age-related shortening of telomeres may offer modifiable means of reducing breast cancer risk.
Publications
Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.
Authors: Mei H.
, Simino J.
, Li L.
, Jiang F.
, Bis J.C.
, Davies G.
, Hill W.D.
, Xia C.
, Gudnason V.
, Yang Q.
, et al.
.
Source: Alzheimer's Research & Therapy, 2024-01-20 00:00:00.0; 16(1), p. 14.
EPub date: 2024-01-20 00:00:00.0.
PMID: 38245754
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Precise diagnosis of three top cancers using dbGaP data.
Authors: Liu X.Q.
, Liu X.S.
, Rong J.Y.
, Gao F.
, Wu Y.D.
, Deng C.H.
, Jiang H.Y.
, Li X.F.
, Chen Y.Q.
, Zhao Z.G.
, et al.
.
Source: Scientific Reports, 2021-01-12 00:00:00.0; 11(1), p. 823.
EPub date: 2021-01-12 00:00:00.0.
PMID: 33436913
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Leukocyte Telomere Length and All-Cause, Cardiovascular Disease, and Cancer Mortality: Results From Individual-Participant-Data Meta-Analysis of 2 Large Prospective Cohort Studies.
Authors: Mons U.
, Müezzinler A.
, Schöttker B.
, Dieffenbach A.K.
, Butterbach K.
, Schick M.
, Peasey A.
, De Vivo I.
, Trichopoulou A.
, Boffetta P.
, et al.
.
Source: American Journal Of Epidemiology, 2017-06-15 00:00:00.0; 185(12), p. 1317-1326.
PMID: 28459963
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PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.
Authors: Southey M.C.
, Goldgar D.E.
, Winqvist R.
, Pylkäs K.
, Couch F.
, Tischkowitz M.
, Foulkes W.D.
, Dennis J.
, Michailidou K.
, van Rensburg E.J.
, et al.
.
Source: Journal Of Medical Genetics, 2016 Dec; 53(12), p. 800-811.
PMID: 27595995
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Coffee Consumption Is Positively Associated with Longer Leukocyte Telomere Length in the Nurses' Health Study.
Authors: Liu J.J.
, Crous-Bou M.
, Giovannucci E.
, De Vivo I.
.
Source: The Journal Of Nutrition, 2016 07; 146(7), p. 1373-8.
EPub date: 2016-06-08 00:00:00.0.
PMID: 27281805
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Gwas For Executive Function And Processing Speed Suggests Involvement Of The Cadm2 Gene
Authors: Ibrahim-Verbaas C.A.
, Bressler J.
, Debette S.
, Schuur M.
, Smith A.V.
, Bis J.C.
, Davies G.
, Trompet S.
, Smith J.A.
, Wolf C.
, et al.
.
Source: Molecular Psychiatry, 2016 Feb; 21(2), p. 189-97.
PMID: 25869804
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Genome-wide Meta-analysis Uncovers Novel Loci Influencing Circulating Leptin Levels
Authors: Kilpeläinen T.O.
, Carli J.F.
, Skowronski A.A.
, Sun Q.
, Kriebel J.
, Feitosa M.F.
, Hedman Å.K.
, Drong A.W.
, Hayes J.E.
, Zhao J.
, et al.
.
Source: Nature Communications, 2016; 7, p. 10494.
PMID: 26833098
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A prospective study of leukocyte telomere length and risk of phobic anxiety among women.
Authors: Ramin C.
, Wang W.
, Prescott J.
, Rosner B.
, Simon N.M.
, De Vivo I.
, Okereke O.I.
.
Source: Psychiatry Research, 2015-12-15 00:00:00.0; 230(2), p. 545-52.
PMID: 26603336
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Genome-wide Studies Of Verbal Declarative Memory In Nondemented Older People: The Cohorts For Heart And Aging Research In Genomic Epidemiology Consortium
Authors: Debette S.
, Ibrahim Verbaas C.A.
, Bressler J.
, Schuur M.
, Smith A.
, Bis J.C.
, Davies G.
, Wolf C.
, Gudnason V.
, Chibnik L.B.
, et al.
.
Source: Biological Psychiatry, 2015-04-15 00:00:00.0; 77(8), p. 749-63.
PMID: 25648963
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Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.
Authors: Lin W.Y.
, Camp N.J.
, Ghoussaini M.
, Beesley J.
, Michailidou K.
, Hopper J.L.
, Apicella C.
, Southey M.C.
, Stone J.
, Schmidt M.K.
, et al.
.
Source: Human Molecular Genetics, 2015-01-01 00:00:00.0; 24(1), p. 285-98.
EPub date: 2015-01-01 00:00:00.0.
PMID: 25168388
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Mediterranean diet and telomere length in Nurses' Health Study: population based cohort study.
Authors: Crous-Bou M.
, Fung T.T.
, Prescott J.
, Julin B.
, Du M.
, Sun Q.
, Rexrode K.M.
, Hu F.B.
, De Vivo I.
.
Source: Bmj (clinical Research Ed.), 2014-12-02 00:00:00.0; 349, p. g6674.
EPub date: 2014-12-02 00:00:00.0.
PMID: 25467028
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Application Of The Rosner-wei Risk-prediction Model To Estimate Sexual Orientation Patterns In Colon Cancer Risk In A Prospective Cohort Of Us Women
Authors: Austin S.B.
, Pazaris M.J.
, Wei E.K.
, Rosner B.
, Kennedy G.A.
, Bowen D.
, Spiegelman D.
.
Source: Cancer Causes & Control : Ccc, 2014 Aug; 25(8), p. 999-1006.
PMID: 24852207
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Microrna Related Polymorphisms And Breast Cancer Risk
Authors: Khan S.
, Greco D.
, Michailidou K.
, Milne R.L.
, Muranen T.A.
, Heikkinen T.
, Aaltonen K.
, Dennis J.
, Bolla M.K.
, Liu J.
, et al.
.
Source: Plos One, 2014; 9(11), p. e109973.
PMID: 25390939
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Genetic Modifiers Of Menopausal Hormone Replacement Therapy And Breast Cancer Risk: A Genome-wide Interaction Study
Authors: Rudolph A.
, Hein R.
, Lindström S.
, Beckmann L.
, Behrens S.
, Liu J.
, Aschard H.
, Bolla M.K.
, Wang J.
, Truong T.
, et al.
.
Source: Endocrine-related Cancer, 2013 Dec; 20(6), p. 875-87.
PMID: 24080446
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Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism In Genetic Loci For Anthropometric Traits
Authors: Randall J.C.
, Winkler T.W.
, Kutalik Z.
, Berndt S.I.
, Jackson A.U.
, Monda K.L.
, Kilpeläinen T.O.
, Esko T.
, Mägi R.
, Li S.
, et al.
.
Source: Plos Genetics, 2013 Jun; 9(6), p. e1003500.
PMID: 23754948
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Imputation Across Genotyping Arrays For Genome-wide Association Studies: Assessment Of Bias And A Correction Strategy
Authors: Johnson E.O.
, Hancock D.B.
, Levy J.L.
, Gaddis N.C.
, Saccone N.L.
, Bierut L.J.
, Page G.P.
.
Source: Human Genetics, 2013 May; 132(5), p. 509-22.
PMID: 23334152
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A nonparametric test to detect quantitative trait loci where the phenotypic distribution differs by genotypes.
Authors: Aschard H.
, Zaitlen N.
, Tamimi R.M.
, Lindström S.
, Kraft P.
.
Source: Genetic Epidemiology, 2013 May; 37(4), p. 323-33.
PMID: 23512279
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A Genome-wide Association Study Of Depressive Symptoms
Authors: Hek K.
, Demirkan A.
, Lahti J.
, Terracciano A.
, Teumer A.
, Cornelis M.C.
, Amin N.
, Bakshis E.
, Baumert J.
, Ding J.
, et al.
.
Source: Biological Psychiatry, 2013-04-01 00:00:00.0; 73(7), p. 667-78.
PMID: 23290196
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A Genome-wide Association Study To Identify Genetic Susceptibility Loci That Modify Ductal And Lobular Postmenopausal Breast Cancer Risk Associated With Menopausal Hormone Therapy Use: A Two-stage Design With Replication
Authors: Hein R.
, Flesch-Janys D.
, Dahmen N.
, Beckmann L.
, Lindström S.
, Schoof N.
, Czene K.
, Mittelstraß K.
, Illig T.
, Seibold P.
, et al.
.
Source: Breast Cancer Research And Treatment, 2013 Apr; 138(2), p. 529-42.
PMID: 23423446
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Large-scale Genotyping Identifies 41 New Loci Associated With Breast Cancer Risk
Authors: Michailidou K.
, Hall P.
, Gonzalez-Neira A.
, Ghoussaini M.
, Dennis J.
, Milne R.L.
, Schmidt M.K.
, Chang-Claude J.
, Bojesen S.E.
, Bolla M.K.
, et al.
.
Source: Nature Genetics, 2013 Apr; 45(4), p. 353-61, 361e1-2.
PMID: 23535729
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An Examination Of Sexual Orientation Group Patterns In Mammographic And Colorectal Screening In A Cohort Of U.s. Women
Authors: Austin S.B.
, Pazaris M.J.
, Nichols L.P.
, Bowen D.
, Wei E.K.
, Spiegelman D.
.
Source: Cancer Causes & Control : Ccc, 2013 Mar; 24(3), p. 539-47.
PMID: 22729931
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Genetic Predisposition To Higher Body Mass Index Or Type 2 Diabetes And Leukocyte Telomere Length In The Nurses' Health Study
Authors: Du M.
, Prescott J.
, Cornelis M.C.
, Hankinson S.E.
, Giovannucci E.
, Kraft P.
, De Vivo I.
.
Source: Plos One, 2013; 8(2), p. e52240.
PMID: 23424613
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A Meta-analysis Of Genome-wide Association Studies Of Breast Cancer Identifies Two Novel Susceptibility Loci At 6q14 And 20q11
Authors: Siddiq A.
, Couch F.J.
, Chen G.K.
, Lindström S.
, Eccles D.
, Millikan R.C.
, Michailidou K.
, Stram D.O.
, Beckmann L.
, Rhie S.K.
, et al.
.
Source: Human Molecular Genetics, 2012-12-15 00:00:00.0; 21(24), p. 5373-84.
PMID: 22976474
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Paternal Age At Birth Is Associated With Offspring Leukocyte Telomere Length In The Nurses' Health Study
Authors: Prescott J.
, Du M.
, Wong J.Y.
, Han J.
, De Vivo I.
.
Source: Human Reproduction (oxford, England), 2012 Dec; 27(12), p. 3622-31.
PMID: 22940768
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Application Of The Rosner-colditz Risk Prediction Model To Estimate Sexual Orientation Group Disparities In Breast Cancer Risk In A U.s. Cohort Of Premenopausal Women
Authors: Austin S.B.
, Pazaris M.J.
, Rosner B.
, Bowen D.
, Rich-Edwards J.
, Spiegelman D.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2012 Dec; 21(12), p. 2201-8.
PMID: 23035180
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Adult Body Mass Index Trajectories And Sexual Orientation: The Nurses' Health Study Ii
Authors: Jun H.J.
, Corliss H.L.
, Nichols L.P.
, Pazaris M.J.
, Spiegelman D.
, Austin S.B.
.
Source: American Journal Of Preventive Medicine, 2012 Apr; 42(4), p. 348-54.
PMID: 22424247
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Fine Mapping Of 14q24.1 Breast Cancer Susceptibility Locus
Authors: Lee P.
, Fu Y.P.
, Figueroa J.D.
, Prokunina-Olsson L.
, Gonzalez-Bosquet J.
, Kraft P.
, Wang Z.
, Jacobs K.B.
, Yeager M.
, Horner M.J.
, et al.
.
Source: Human Genetics, 2012 Mar; 131(3), p. 479-90.
PMID: 21959381
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Epidemiologic Evidence For A Role Of Telomere Dysfunction In Cancer Etiology
Authors: Prescott J.
, Wentzensen I.M.
, Savage S.A.
, De Vivo I.
.
Source: Mutation Research, 2012-02-01 00:00:00.0; 730(1-2), p. 75-84.
PMID: 21756922
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High Phobic Anxiety Is Related To Lower Leukocyte Telomere Length In Women
Authors: Okereke O.I.
, Prescott J.
, Wong J.Y.
, Han J.
, Rexrode K.M.
, De Vivo I.
.
Source: Plos One, 2012; 7(7), p. e40516.
PMID: 22808180
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Genome-wide Association Study Of Relative Telomere Length
Authors: Prescott J.
, Kraft P.
, Chasman D.I.
, Savage S.A.
, Mirabello L.
, Berndt S.I.
, Weissfeld J.L.
, Han J.
, Hayes R.B.
, Chanock S.J.
, et al.
.
Source: Plos One, 2011; 6(5), p. e19635.
PMID: 21573004
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The Mediating Effect Of Childhood Abuse In Sexual Orientation Disparities In Tobacco And Alcohol Use During Adolescence: Results From The Nurses' Health Study Ii
Authors: Jun H.J.
, Austin S.B.
, Wylie S.A.
, Corliss H.L.
, Jackson B.
, Spiegelman D.
, Pazaris M.J.
, Wright R.J.
.
Source: Cancer Causes & Control : Ccc, 2010 Nov; 21(11), p. 1817-28.
PMID: 20640883
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Meta-analysis Identifies 13 New Loci Associated With Waist-hip Ratio And Reveals Sexual Dimorphism In The Genetic Basis Of Fat Distribution
Authors: Heid I.M.
, Jackson A.U.
, Randall J.C.
, Winkler T.W.
, Qi L.
, Steinthorsdottir V.
, Thorleifsson G.
, Zillikens M.C.
, Speliotes E.K.
, Mägi R.
, et al.
.
Source: Nature Genetics, 2010 Nov; 42(11), p. 949-60.
PMID: 20935629
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Association Analyses Of 249,796 Individuals Reveal 18 New Loci Associated With Body Mass Index
Authors: Speliotes E.K.
, Willer C.J.
, Berndt S.I.
, Monda K.L.
, Thorleifsson G.
, Jackson A.U.
, Lango Allen H.
, Lindgren C.M.
, Luan J.
, Mägi R.
, et al.
.
Source: Nature Genetics, 2010 Nov; 42(11), p. 937-48.
PMID: 20935630
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Hundreds Of Variants Clustered In Genomic Loci And Biological Pathways Affect Human Height
Authors: Lango Allen H.
, Estrada K.
, Lettre G.
, Berndt S.I.
, Weedon M.N.
, Rivadeneira F.
, Willer C.J.
, Jackson A.U.
, Vedantam S.
, Raychaudhuri S.
, et al.
.
Source: Nature, 2010-10-14 00:00:00.0; 467(7317), p. 832-8.
PMID: 20881960
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Genetic Variation In The Estrogen Metabolic Pathway And Mammographic Density As An Intermediate Phenotype Of Breast Cancer
Authors: Li J.
, Eriksson L.
, Humphreys K.
, Czene K.
, Liu J.
, Tamimi R.M.
, Lindström S.
, Hunter D.J.
, Vachon C.M.
, Couch F.J.
, et al.
.
Source: Breast Cancer Research : Bcr, 2010; 12(2), p. R19.
PMID: 20214802
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Genome-wide Significant Predictors Of Metabolites In The One-carbon Metabolism Pathway
Authors: Hazra A.
, Kraft P.
, Lazarus R.
, Chen C.
, Chanock S.J.
, Jacques P.
, Selhub J.
, Hunter D.J.
.
Source: Human Molecular Genetics, 2009-12-01 00:00:00.0; 18(23), p. 4677-87.
PMID: 19744961
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Caffeinated And Alcoholic Beverage Intake In Relation To Ovulatory Disorder Infertility
Authors: Chavarro J.E.
, Rich-Edwards J.W.
, Rosner B.A.
, Willett W.C.
.
Source: Epidemiology (cambridge, Mass.), 2009 May; 20(3), p. 374-81.
PMID: 19279491
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Newly Discovered Breast Cancer Susceptibility Loci On 3p24 And 17q23.2
Authors: Ahmed S.
, Thomas G.
, Ghoussaini M.
, Healey C.S.
, Humphreys M.K.
, Platte R.
, Morrison J.
, Maranian M.
, Pooley K.A.
, Luben R.
, et al.
.
Source: Nature Genetics, 2009 May; 41(5), p. 585-90.
PMID: 19330027
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A Multistage Genome-wide Association Study In Breast Cancer Identifies Two New Risk Alleles At 1p11.2 And 14q24.1 (rad51l1)
Authors: Thomas G.
, Jacobs K.B.
, Kraft P.
, Yeager M.
, Wacholder S.
, Cox D.G.
, Hankinson S.E.
, Hutchinson A.
, Wang Z.
, Yu K.
, et al.
.
Source: Nature Genetics, 2009 May; 41(5), p. 579-84.
PMID: 19330030
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A Prospective Study Of Relative Telomere Length And Postmenopausal Breast Cancer Risk
Authors: De Vivo I.
, Prescott J.
, Wong J.Y.
, Kraft P.
, Hankinson S.E.
, Hunter D.J.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2009 Apr; 18(4), p. 1152-6.
PMID: 19293310
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Association Of Esr1 Gene Tagging Snps With Breast Cancer Risk
Authors: Dunning A.M.
, Healey C.S.
, Baynes C.
, Maia A.T.
, Scollen S.
, Vega A.
, Rodríguez R.
, Barbosa-Morais N.L.
, Ponder B.A.
, SEARCH
, et al.
.
Source: Human Molecular Genetics, 2009-03-15 00:00:00.0; 18(6), p. 1131-9.
PMID: 19126777
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A prospective study of genetic polymorphism in MPO, antioxidant status, and breast cancer risk.
Authors: He C.
, Tamimi R.M.
, Hankinson S.E.
, Hunter D.J.
, Han J.
.
Source: Breast Cancer Research And Treatment, 2009 Feb; 113(3), p. 585-94.
PMID: 18340529
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A Prospective Study Of Dietary Carbohydrate Quantity And Quality In Relation To Risk Of Ovulatory Infertility
Authors: Chavarro J.E.
, Rich-Edwards J.W.
, Rosner B.A.
, Willett W.C.
.
Source: European Journal Of Clinical Nutrition, 2009 Jan; 63(1), p. 78-86.
PMID: 17882137
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Six New Loci Associated With Body Mass Index Highlight A Neuronal Influence On Body Weight Regulation
Authors: Willer C.J.
, Speliotes E.K.
, Loos R.J.
, Li S.
, Lindgren C.M.
, Heid I.M.
, Berndt S.I.
, Elliott A.L.
, Jackson A.U.
, Lamina C.
, et al.
.
Source: Nature Genetics, 2009 Jan; 41(1), p. 25-34.
PMID: 19079261
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The mitochondrial A10398G polymorphism, interaction with alcohol consumption, and breast cancer risk.
Authors: Pezzotti A.
, Kraft P.
, Hankinson S.E.
, Hunter D.J.
, Buring J.
, Cox D.G.
.
Source: Plos One, 2009; 4(4), p. e5356.
PMID: 19390621
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Common Variants Of Fut2 Are Associated With Plasma Vitamin B12 Levels
Authors: Hazra A.
, Kraft P.
, Selhub J.
, Giovannucci E.L.
, Thomas G.
, Hoover R.N.
, Chanock S.J.
, Hunter D.J.
.
Source: Nature Genetics, 2008 Oct; 40(10), p. 1160-2.
PMID: 18776911
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Population Substructure And Control Selection In Genome-wide Association Studies
Authors: Yu K.
, Wang Z.
, Li Q.
, Wacholder S.
, Hunter D.J.
, Hoover R.N.
, Chanock S.
, Thomas G.
.
Source: Plos One, 2008-07-02 00:00:00.0; 3(7), p. e2551.
PMID: 18596976
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Disparities In Child Abuse Victimization In Lesbian, Bisexual, And Heterosexual Women In The Nurses' Health Study Ii
Authors: Austin S.B.
, Jun H.J.
, Jackson B.
, Spiegelman D.
, Rich-Edwards J.
, Corliss H.L.
, Wright R.J.
.
Source: Journal Of Women's Health (2002), 2008 May; 17(4), p. 597-606.
PMID: 18447763
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Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy.
Authors: Grodstein F.
, Manson J.E.
, Stampfer M.J.
, Rexrode K.
.
Source: Archives Of Internal Medicine, 2008-04-28 00:00:00.0; 168(8), p. 861-6.
PMID: 18443262
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Comprehensive association testing of common genetic variation in DNA repair pathway genes in relationship with breast cancer risk in multiple populations.
Authors: Haiman C.A.
, Hsu C.
, de Bakker P.I.
, Frasco M.
, Sheng X.
, Van Den Berg D.
, Casagrande J.T.
, Kolonel L.N.
, Le Marchand L.
, Hankinson S.E.
, et al.
.
Source: Human Molecular Genetics, 2008-03-15 00:00:00.0; 17(6), p. 825-34.
EPub date: 2008-03-15 00:00:00.0.
PMID: 18056155
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