Meta-Analysis

. 2016 Nov;25(11):1503-1510.

doi: 10.1158/1055-9965.EPI-16-0147. 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

Jodie N Painter¹, Tracy A O'Mara¹, Louise Marquart¹, Penelope M Webb, John Attia^{2

3}, Sarah E Medland¹, Timothy Cheng⁴, Joe Dennis⁵, Elizabeth G Holliday^{2

3}, Mark McEvoy³, Rodney J Scott^{2

6

7

8}, Shahana Ahmed⁹, Catherine S Healey⁹, Mitul Shah⁹, Maggie Gorman⁴, Lynn Martin⁴, Shirley V Hodgson¹⁰, Matthias W Beckmann¹¹, Arif B Ekici¹², Peter A Fasching^{11

13}, Alexander Hein¹¹, Matthias Rübner¹¹, Kamila Czene¹⁴, Hatef Darabi¹⁴, Per Hall¹⁴, Jingmei Li¹⁴, Thilo Dörk¹⁵, Matthias Dürst¹⁶, Peter Hillemanns¹⁷, Ingo B Runnebaum¹⁶, Frederic Amant¹⁸, Daniela Annibali¹⁸, Jeroen Depreeuw^{18

19

20}, Diether Lambrechts^{19

20}, Patrick Neven¹⁸, Julie M Cunningham²¹, Sean C Dowdy²², Ellen L Goode²³, Brooke L Fridley²⁴, Stacey J Winham²³, Tormund S Njølstad^{25

26}, Helga B Salvesen^{25

26}, Jone Trovik^{25

26}, Henrica M J Werner^{25

26}, Katie A Ashton^{2

7

8}, Geoffrey Otton²⁷, Anthony Proietto²⁷, Miriam Mints²⁸, Emma Tham, Manjeet K Bolla⁵, Kyriaki Michailidou⁵, Qin Wang⁵, Jonathan P Tyrer⁹, John L Hopper²⁹, Julian Peto³⁰, Anthony J Swerdlow^{31

32}, Barbara Burwinkel^{33

34}, Hermann Brenner^{35

36

37}, Alfons Meindl³⁸, Hiltrud Brauch^{37

39

40}, Annika Lindblom⁴¹, Jenny Chang-Claude^{42

43}, Fergus J Couch^{21

23}, Graham G Giles^{29

44

45}, Vessela N Kristensen^{46

47

48}, Angela Cox⁴⁹, Paul D P Pharoah⁹, Ian Tomlinson⁴, Alison M Dunning⁹, Douglas F Easton^{5

9}, Deborah J Thompson, Amanda B Spurdle; AOCS Group; for RENDOCAS; National Study of Endometrial Cancer Genetics Group (NSECG); Australian National Endometrial Cancer Study Group (ANECS)

Affiliations

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.

PMID: 27550749
PMCID: PMC5093082
DOI: 10.1158/1055-9965.EPI-16-0147

Meta-Analysis

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

Jodie N Painter et al. Cancer Epidemiol Biomarkers Prev. 2016 Nov.

. 2016 Nov;25(11):1503-1510.

doi: 10.1158/1055-9965.EPI-16-0147. Epub 2016 Aug 22.

Authors

Affiliations

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.

PMID: 27550749
PMCID: PMC5093082
DOI: 10.1158/1055-9965.EPI-16-0147

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.

PubMed Disclaimer

Conflict of interest statement

Statement: No potential conflicts of interest were disclosed by the other authors.

Figures

**Figure 1. Observed and predicted risks of increasing BMI on endometrial cancer**
The predicted effect of a 5kg/m² increase in BMI on EC risk was estimated by scaling the effect of the per weighted allele increase in the BMIwGRS on BMI (4.83 kg/m²) by the effect of the per weighted allele increase in the BMIwGRS on EC (OR 2.11) in our dataset (exp[(4.83/5)*ln(2.11)]). The predicted effect (grey arrow) of a per 5kg/m² increase in BMI on endometrial cancer risk (OR 2.06) is larger than that observed in our study (OR 1.55).

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical