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Cancer Epidemiol Biomarkers Prev. 2016 Nov;25(11):1503-1510. Epub 2016 Aug 22.

Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer.

Author information

1
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
2
Hunter Medical Research Institute, John Hunter Hospital, Newcastle, Australia.
3
Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Australia.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
5
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
6
Hunter Area Pathology Service, John Hunter Hospital, Newcastle, Australia.
7
Centre for Information Based Medicine, University of Newcastle, Australia.
8
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
9
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
10
Department of Clinical Genetics, St George's, University of London, London, United Kingdom.
11
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
12
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
13
Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
14
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
15
Hannover Medical School, Gynaecology Research Unit, Hannover, Germany.
16
Department of Gynaecology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
17
Hannover Medical School, Clinics of Gynaecology and Obstetrics, Hannover, Germany.
18
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven - University of Leuven, Leuven, Belgium.
19
Vesalius Research Center, VIB, Leuven, Belgium.
20
Department of Oncology, Laboratory for Translational Genetics, University Hospitals Leuven, Leuven, Belgium.
21
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
22
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo Clinic, Rochester, Minnesota.
23
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
24
Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas.
25
Department of Clinical Science, Centre for Cancer Biomarkers, The University of Bergen, Bergen, Norway.
26
Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
27
School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.
28
Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
29
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
30
London School of Hygiene and Tropical Medicine, London, United Kingdom.
31
Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom.
32
Division of Breast Cancer Research, Institute of Cancer Research, London, United Kingdom.
33
Department of Gynecology and Obstetrics, Molecular Biology of Breast Cancer, University of Heidelberg, Heidelberg, Germany.
34
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
35
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
36
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
37
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
38
Department of Obstetrics and Gynecology, Division of Tumor Genetics, Technical University of Munich, Munich, Germany.
39
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
40
University of Tübingen, Tübingen, Germany.
41
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
42
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
43
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
44
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
45
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
46
Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.
47
The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
48
Department of Clinical Molecular Oncology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway.
49
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, United Kingdom.

Abstract

BACKGROUND:

The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls.

METHODS:

Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable.

RESULTS:

The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS.

CONCLUSIONS:

BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI.

IMPACT:

The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.

PMID:
27550749
PMCID:
PMC5093082
DOI:
10.1158/1055-9965.EPI-16-0147
[Indexed for MEDLINE]
Free PMC Article

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