A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes.
We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with type 2 diabetes were ascertained. Higher uric acid was associated with a higher diabetes risk after adjustment for confounders, with a hazard ratio (HR) of 1.20 (95% CI 1.11, 1.30) per 59.48 µmol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 µmol/L (95% CI 15, 18) per SD increase and explained 4% of uric acid variation. By using the genetic score to estimate the unconfounded effect, we found that a 59.48 µmol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01 [95% CI 0.87, 1.16]). Including data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 41,508 case subjects with diabetes, the summary odds ratio estimate was 0.99 (95% CI 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid-lowering therapies may therefore not be beneficial in reducing diabetes risk.
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands i.sluijs-2@umcutrecht.nl.
Ivonne
I
Sluijs
Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, U.K. Division of Transplantation and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Michael V
MV
Holmes
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
Yvonne T
YT
van der Schouw
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
Joline W J
JW
Beulens
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands Department of Cardiology, Heart Long Institute, University Medical Center Utrecht, Utrecht, the Netherlands Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands.
Folkert W
FW
Asselbergs
Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
José María
JM
Huerta
Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K.
Tom M
TM
Palmer
CIBER Epidemiología y Salud Pública (CIBERESP), Spain Public Health Division of Gipuzkoa, San Sebastian, Spain Instituto BIO-Donostia, Basque Government, San Sebastian, Spain.
Larraitz
L
Arriola
Inserm, Center for Research in Epidemiology and Population Health (CESP), U1018, Villejuif, France Université Paris-Sud, UMRS 1018, Villejuif, France.
Beverley
B
Balkau
CIBER Epidemiología y Salud Pública (CIBERESP), Spain Navarre Public Health Institute (ISPN), Pamplona, Spain.
Aurelio
A
Barricarte
German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
Heiner
H
Boeing
Inserm, Center for Research in Epidemiology and Population Health (CESP), U1018, Villejuif, France Université Paris-Sud, UMRS 1018, Villejuif, France.
Françoise
F
Clavel-Chapelon
Inserm, Center for Research in Epidemiology and Population Health (CESP), U1018, Villejuif, France Université Paris-Sud, UMRS 1018, Villejuif, France.
Guy
G
Fagherazzi
Lund University, Malmö, Sweden Umeå University, Umeå, Sweden.
Paul W
PW
Franks
Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
Diana
D
Gavrila
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Rudolf
R
Kaaks
University of Cambridge, Cambridge, U.K.
Kay Tee
KT
Khaw
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Tilman
T
Kühn
CIBER Epidemiología y Salud Pública (CIBERESP), Spain Andalusian School of Public Health, Granada, Spain.
Esther
E
Molina-Montes
Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
Lotte Maxild
LM
Mortensen
Lund University, Malmö, Sweden.
Peter M
PM
Nilsson
Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark Aalborg University Hospital, Aalborg, Denmark.
Kim
K
Overvad
Cancer Research and Prevention Institute (ISPO), Florence, Italy.
Domenico
D
Palli
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
Salvatore
S
Panico
Public Health Directorate, Asturias, Spain.
J Ramón
JR
Quirós
Umeå University, Umeå, Sweden.
Olov
O
Rolandsson
Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital, University of Turin and Center for Cancer Prevention (CPO), Turin, Italy Human Genetics Foundation (HuGeF), Turin, Italy.
Carlotta
C
Sacerdote
Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, and Translational Research Laboratory, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain.
Núria
N
Sala
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.
Julie A
JA
Schmidt
MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
Robert A
RA
Scott
Epidemiology and Prevention Unit, Milan, Italy.
Sabina
S
Sieri
International Agency for Research on Cancer, Lyon, France.
Nadia
N
Slimani
National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
Annemieke M W
AM
Spijkerman
Danish Cancer Society Research Center, Copenhagen, Denmark.
Anne
A
Tjonneland
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.
Ruth C
RC
Travis
ASP Ragusa, Ragusa, Italy AIRE ONLUS, Ragusa, Italy.
Rosario
R
Tumino
National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
Daphne L
DL
van der A
MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
Stephen J
SJ
Sharp
MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
Nita G
NG
Forouhi
MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
Claudia
C
Langenberg
School of Public Health, Imperial College London, U.K.
Elio
E
Riboli
MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
Nicholas J
NJ
Wareham
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D011446:Prospective Studies; D014527:Uric Acid / Q000097:blood*
D014527:Uric Acid