title: Five endometrial cancer risk loci identified through genome-wide association analysis.
abstract: We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.initials: TH
authors.lastname: Cheng
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Thompson
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: O'Mara
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Jodie N
authors.initials: JN
authors.lastname: Painter
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Dylan M
authors.initials: DM
authors.lastname: Glubb
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Susanne
authors.initials: S
authors.lastname: Flach
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Annabelle
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authors.lastname: Lewis
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Juliet D
authors.initials: JD
authors.lastname: French
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Freeman-Mills
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Church
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Maggie
authors.initials: M
authors.lastname: Gorman
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Lynn
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authors.lastname: Martin
authors.affiliation: Department of Clinical Genetics, St George's, University of London, London, UK.
authors.forename: Shirley
authors.initials: S
authors.lastname: Hodgson
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Webb
authors.affiliation: Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia.|Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, NSW, Australia.
authors.forename: John
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authors.lastname: Attia
authors.affiliation: Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia.|Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, NSW, Australia.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Holliday
authors.affiliation: Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, NSW, Australia.
authors.forename: Mark
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authors.lastname: McEvoy
authors.affiliation: Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia.|Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia.|Centre for Information Based Medicine, University of Newcastle, NSW, Australia.|School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Shahana
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authors.lastname: Ahmed
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
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authors.initials: CS
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Mitul
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Joe
authors.initials: J
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authors.affiliation: University of California at Los Angeles, Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, Los Angeles, CA, USA.|Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hein
authors.affiliation: Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
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authors.lastname: Hall
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hatef
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jingmei
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authors.affiliation: Hannover Medical School, Gynaecology Research Unit, Hannover, Germany.
authors.forename: Thilo
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authors.lastname: Dörk
authors.affiliation: Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany.
authors.forename: Matthias
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authors.lastname: Dürst
authors.affiliation: Hannover Medical School, Clinics of Gynaecology and Obstetrics, Hannover, Germany.
authors.forename: Peter
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authors.lastname: Hillemanns
authors.affiliation: Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Runnebaum
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Amant
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Belgium.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schrauwen
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Belgium.|Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
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authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo Clinic, Rochester, MN, USA.
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authors.initials: SC
authors.lastname: Dowdy
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
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authors.initials: EL
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authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Winham
authors.affiliation: Centre for Cancerbiomarkers, Department of Clinical Science, The University of Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
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authors.initials: TS
authors.lastname: Njølstad
authors.affiliation: Centre for Cancerbiomarkers, Department of Clinical Science, The University of Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.affiliation: Centre for Cancerbiomarkers, Department of Clinical Science, The University of Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Jone
authors.initials: J
authors.lastname: Trovik
authors.affiliation: Centre for Cancerbiomarkers, Department of Clinical Science, The University of Bergen, Norway.|Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Henrica Mj
authors.initials: HM
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authors.affiliation: Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia.|Centre for Information Based Medicine, University of Newcastle, NSW, Australia.|School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.
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authors.initials: K
authors.lastname: Ashton
authors.affiliation: School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia.
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authors.affiliation: School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia.
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authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tao
authors.initials: T
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authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Miriam
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authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Clinical Genetics, Karolinska University Hospital Solna, Stockholm, Sweden.
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authors.lastname: Tham
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|A list of members and affiliations appears in the Supplementary Note.
authors.forename: Chibcha
authors.initials: C
authors.lastname: Consortium
authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Mulin
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authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
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authors.initials: SH
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authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
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authors.initials: MK
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
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authors.initials: K
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
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authors.initials: Q
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
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authors.initials: JP
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authors.affiliation: Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|MRC Human Genetics Unit, Western General Hospital Edinburgh, Edinburgh, UK.
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authors.initials: M
authors.lastname: Dunlop
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Houlston
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Vic, Australia.
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authors.initials: JL
authors.lastname: Hopper
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Peto
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.|Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Swerdlow
authors.affiliation: Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany.|Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Department of Obstetrics and Gynecology, Division of Tumor Genetics, Technical University of Munich, Munich, Germany.
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.affiliation: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.|Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.|Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
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authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Vic, Australia.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Vic, Australia.|Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.|Department of Clinical Molecular Oncology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.affiliation: Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Paul D P
authors.initials: PDP
authors.lastname: Pharoah
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Edwards
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
mesh_terms: D002898:Chromosomes, Human, Pair 8; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic