The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.
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Ghislaine
Scelo
;
Mark P
Purdue
;
Daniela
Mariosa
;
David C
Muller
;
Nicolas J
Timpson
;
Philip C
Haycock
;
Kevin M
Brown
;
Zhaoming
Wang
;
+103 more...
Yuanqing
Ye
;
Jonathan N
Hofmann
;
Matthieu
Foll
;
Valerie
Gaborieau
;
Mitchell J
Machiela
;
Leandro M
Colli
;
Peng
Li
;
Jean-Guillaume
Garnier
;
Helene
Blanche
;
Anne
Boland
;
Laurie
Burdette
;
Egor
Prokhortchouk
;
Konstantin G
Skryabin
;
Meredith
Yeager
;
Sanja
Radojevic-Skodric
;
Simona
Ognjanovic
;
Lenka
Foretova
;
Ivana
Holcatova
;
Vladimir
Janout
;
Dana
Mates
;
Anush
Mukeriya
;
Stefan
Rascu
;
David
Zaridze
;
Vladimir
Bencko
;
Cezary
Cybulski
;
Eleonora
Fabianova
;
Viorel
Jinga
;
Jolanta
Lissowska
;
Jan
Lubinski
;
Marie
Navratilova
;
Peter
Rudnai
;
Simone
Benhamou
;
Geraldine
Cancel-Tassin
;
Olivier
Cussenot
;
Elisabete
Weiderpass
;
Börje
Ljungberg
;
Raviprakash
Tumkur Sitaram
;
Christel
Häggström
;
Fiona
Bruinsma
;
Susan J
Jordan
;
Gianluca
Severi
;
Ingrid
Winship
;
Kristian
Hveem
;
Lars J
Vatten
;
Tony
Fletcher
;
Susanna C
Larsson
;
Alicja
Wolk
;
Rosamonde E
Banks
;
Peter J
Selby
;
Douglas F
Easton
;
Gabriella
Andreotti
;
Laura E
Beane Freeman
;
Stella
Koutros
;
Satu
Männistö
;
Stephanie
Weinstein
;
Peter E
Clark
;
Todd L
Edwards
;
Loren
Lipworth
;
Susan M
Gapstur
;
Victoria L
Stevens
;
Hallie
Carol
;
Matthew L
Freedman
;
Mark M
Pomerantz
;
Eunyoung
Cho
;
Kathryn M
Wilson
;
J Michael
Gaziano
;
Howard D
Sesso
;
Neal D
Freedman
;
Alexander S
Parker
;
Jeanette E
Eckel-Passow
;
Wen-Yi
Huang
;
Richard J
Kahnoski
;
Brian R
Lane
;
Sabrina L
Noyes
;
David
Petillo
;
Bin Tean
Teh
;
Ulrike
Peters
;
Emily
White
;
Garnet L
Anderson
;
Lisa
Johnson
;
Juhua
Luo
;
Julie
Buring
;
I-Min
Lee
;
Wong-Ho
Chow
;
Lee E
Moore
;
Timothy
Eisen
;
Marc
Henrion
;
James
Larkin
;
Poulami
Barman
;
Bradley C
Leibovich
;
Toni K
Choueiri
;
G Mark
Lathrop
;
Jean-Francois
Deleuze
;
Marc
Gunter
;
James D
McKay
;
Xifeng
Wu
;
Richard S
Houlston
;
Stephen J
Chanock
;
Caroline
Relton
;
J Brent
Richards
;
Richard M
Martin
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George
Davey Smith
;
Paul
Brennan
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(2019)
The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.
PLOS MEDICINE, 16 (1).
e1002724-.
ISSN 1549-1676
DOI: 10.1371/journal.pmed.1002724
BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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