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

被引：62

作者：

Painter, Jodie N. ^{[1
]}

O'Mara, Tracy A. ^{[1
]}

Marquart, Louise ^{[1
]}

Webb, Penelope M. ^{[1
]}

Attia, John ^{[2
,3
]}

Medland, Sarah E. ^{[1
]}

Cheng, Timothy ^{[4
]}

Dennis, Joe ^{[5
]}

Holliday, Elizabeth G. ^{[2
,3
]}

McEvoy, Mark ^{[3
]}

Scott, Rodney J. ^{[2
,6
,7
,8
]}

Ahmed, Shahana ^{[9
]}

Healey, Catherine S. ^{[9
]}

Shah, Mitul ^{[9
]}

Gorman, Maggie ^{[4
]}

Martin, Lynn ^{[4
]}

Hodgson, Shirley V. ^{[10
]}

Beckmann, Matthias W. ^{[11
]}

Ekici, Arif B. ^{[12
]}

Fasching, Peter A. ^{[11
,13
]}

Hein, Alexander ^{[11
]}

Ruebner, Matthias ^{[11
]}

Czene, Kamila ^{[14
]}

Darabi, Hatef ^{[14
]}

Hall, Per ^{[14
]}

Li, Jingmei ^{[14
]}

Doerk, Thilo ^{[15
]}

Duerst, Matthias ^{[16
]}

Hillemanns, Peter ^{[17
]}

Runnebaum, Ingo B. ^{[16
]}

Amant, Frederic ^{[18
]}

Annibali, Daniela ^{[18
]}

Depreeuw, Jeroen ^{[18
,19
,20
]}

Lambrechts, Diether ^{[19
,20
]}

Neven, Patrick ^{[18
]}

Cunningham, Julie M. ^{[21
]}

Dowdy, Sean C. ^{[22
]}

Goode, Ellen L. ^{[23
]}

Fridley, Brooke L. ^{[24
]}

Winham, Stacey J. ^{[23
]}

Njolstad, Tormund S. ^{[25
,26
]}

Salvesen, Helga B. ^{[25
,26
]}

Trovik, Jone ^{[25
,26
]}

Werner, Henrica M. J. ^{[25
,26
]}

Ashton, Katie A. ^{[2
,7
,8
]}

Otton, Geoffrey ^{[27
]}

Proietto, Anthony ^{[27
]}

Mints, Miriam ^{[28
]}

Tham, Emma ^{[29
,30
]}

Bolla, Manjeet K. ^{[5
]}

机构：

[1] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia

[2] John Hunter Hosp, Hunter Med Res Inst, Newcastle, NSW, Australia

[3] Univ Newcastle, Sch Med & Publ Hlth, Ctr Clin Epidemiol & Biostat, Callaghan, NSW 2308, Australia

[4] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[5] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England

[6] John Hunter Hosp, Hunter Area Pathol Serv, Newcastle, NSW, Australia

[7] Univ Newcastle, Ctr Informat Based Med, Callaghan, NSW 2308, Australia

[8] Univ Newcastle, Sch Pharm & Biomed Sci, Callaghan, NSW 2308, Australia

[9] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England

[10] St Georges Univ London, Dept Clin Genet, London, England

[11] Friedrich Alexander Univ Erlangen Nuremberg, Dept Gynecol & Obstet, Erlangen, Germany

[12] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Inst Human Genet, Erlangen, Germany

[13] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol Oncol, Dept Med, Los Angeles, CA 90095 USA

[14] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[15] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany

[16] Friedrich Schiller Univ, Jena Univ Hosp, Dept Gynaecol, Jena, Germany

[17] Hannover Med Sch, Clin Gynaecol & Obstet, Hannover, Germany

[18] Univ Leuven, KU Leuven,Univ Hosp, Div Gynecol Oncol, Dept Obstet & Gynecol, Leuven, Belgium

[19] VIB, Vesalius Res Ctr, Leuven, Belgium

[20] Univ Hosp Leuven, Lab Translat Genet, Dept Oncol, Leuven, Belgium

[21] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[22] Div Gynecol Oncol, Mayo Clin, Dept Obstet & Gynecol, Rochester, MN USA

[23] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[24] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA

[25] Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen, Norway

[26] Haukeland Hosp, Dept Obstet & Gynecol, Bergen, Norway

[27] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia

[28] Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden

[29] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[30] Karolinska Univ Hosp Solna, Clin Genet, Stockholm, Sweden

[31] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia

[32] London Sch Hyg & Trop Med, London, England

[33] Inst Canc Res, Div Genet & Epidemiol, London, England

[34] Inst Canc Res, Div Breast Canc Res, London, England

[35] Heidelberg Univ, Dept Gynecol & Obstet, Mol Biol Breast Canc, Heidelberg, Germany

[36] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany

[37] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[38] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany

[39] Natl Ctr Tumor Dis NCT, Heidelberg, Germany

[40] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[41] Tech Univ Munich, Div Tumor Genet, Dept Obstet & Gynecol, Munich, Germany

[42] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany

[43] Univ Tubingen, Tubingen, Germany

[44] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[45] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany

[46] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia

[47] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia

[48] Norwegian Radium Hosp, Inst Canc Res, Dept Genet, Oslo, Norway

[49] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Fac Med, Oslo, Norway

[50] Akershus Univ Hosp, Div Med, Dept Clin Mol Oncol, Lorenskog, Norway

来源：

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION | 2016年 / 25卷 / 11期

基金：

加拿大健康研究院; 澳大利亚国家健康与医学研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; FAT DISTRIBUTION; ANTHROPOMETRIC MEASURES; COLORECTAL-CANCER; LOCI; METAANALYSIS; VARIANTS; ADIPOSITY; SUBTYPES; BIOLOGY;

D O I：

10.1158/1055-9965.EPI-16-0147

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 WHRSNPs, (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 x 10(-17)). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m(2) 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/m(2)). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 x 10(-4)). There was evidence of directional pleiotropy (P = 1.5 x 10(-4)). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 x 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. (C) 2016 AACR.

引用

页码：1503 / 1510

页数：8

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