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Trans-Ethnic Mendelian Randomization Study Reveals Causal Relationships Between Cardiometabolic Factors and Chronic Kidney Disease

27 Pages Posted: 17 Jun 2021

See all articles by Jie Zheng

Jie Zheng

University of Bristol - Medical Research Council Integrative Epidemiology Unit

Yue-Miao Zhang

Peking University - Key Laboratory of Renal Disease

Humaira Rasheed

University of Bristol - Medical Research Council Integrative Epidemiology Unit

Venexia Walker

University of Bristol - Medical Research Council Integrative Epidemiology Unit

Yuka Sugawara

University of Tokyo Hospital - Division of Nephrology and Endocrinology

JiaChen Li

Peking University - Department of Epidemiology and Biostatistics

Yue Leng

University of California, San Francisco (UCSF) - Department of Psychiatry, Neurology and Epidemiology

Benjamin Elsworth

University of Bristol - MRC Integrative Epidemiology Unit

Robyn E. Wootton

University of Bristol - MRC Integrative Epidemiology Unit

Si Fang

University of Bristol - MRC Integrative Epidemiology Unit

Qian Yang

University of Bristol - Medical Research Council Integrative Epidemiology Unit

Stephen Burgess

University of Cambridge - MRC Biostatistics Unit

Philip C. Haycock

University of Bristol - MRC Integrative Epidemiology Unit

Maria Carolina Borges

University of Bristol - MRC Integrative Epidemiology Unit

Yoonsu Cho

University of Bristol - MRC Integrative Epidemiology Unit

Rebecca Carnegie

University of Bristol - MRC Integrative Epidemiology Unit

Amy Howell

University of Bristol - Medical Research Council Integrative Epidemiology Unit

Jamie Robinson

University of Bristol - Medical Research Council Integrative Epidemiology Unit

Laurent F. Thomas

Norwegian University of Science and Technology (NTNU) - K.G. Jebsen Center for Genetic Epidemiology

Ben Michael Brumpton

University of Bristol - MRC Integrative Epidemiology Unit

Kristian Hveem

Norwegian University of Science and Technology (NTNU) - K.G. Jebsen Center for Genetic Epidemiology

Stein Hallan

Norwegian University of Science and Technology (NTNU) - Department of Clinical and Molecular Medicine

Nora Franceschini

University of North Carolina (UNC) at Chapel Hill - Department of Epidemiology

Andrew P. Morris

The University of Manchester

Anna Köttgen

University of Freiburg - Institute of Genetic Epidemiology

Cristian Pattaro

EURAC Research

Matthias Wuttke

University of Freiburg - Institute of Genetic Epidemiology

Masayuki Yamamoto

Tohoku University - Department of Medical Biochemistry

Naoki Kashihara

Kawasaki Medical School - Department of Nephrology and Hypertension

Masato Akiyama

RIKEN Center for Integrative Medical Sciences - Laboratory for Statistical Analysis

Masahiro Kanai

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Koichi Matsuda

University of Tokyo, Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences

Yoichiro Kamatani

RIKEN Center for Integrative Medical Sciences

Yukinori Okada

Osaka University - Department of Statistical Genetics

Robin Walters

University of Oxford

Iona Y. Millwood

University of Oxford

Zhengming Chen

University of Oxford - Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU)

George Davey Smith

University of Bristol - MRC Integrative Epidemiology Unit; Social Medicine, University of Bristol

Sean Barbour

University of British Columbia (UBC) - Division of Nephrology; University of British Columbia (UBC) - Division of Nephrology

Canqing Yu

Peking University Health Science Center - School of Public Health

Bjørn Olav Åsvold

K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology

Hong Zhang

Peking University - Renal Division

Tom R. Gaunt

University of Bristol - MRC Integrative Epidemiology Unit

More...

Abstract

Background: The chronic kidney disease (CKD) public health burden has not declined as expected with current interventions on treatments focusing only on the disease. This study aims to systematically estimate the causal roles of cardiometabolic risk factors on CKD in Europeans and East Asians using Mendelian randomization (MR).

Methods: A total of 45 risk factors with genetic data in Europeans and 17 risk factors in East Asians were identified as exposures from PubMed. A total of 51,672 CKD cases and 958,102 controls in Europeans and 13,093 CKD cases and 238,118 controls of East Asian ancestry were used as outcome for this study. We defined the CKD case by clinical diagnosis or by estimated glomerular filtration rate (eGFR)<60 ml/min/1·73m2.

Findings: Eight risk factors showed causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asian ancestry, BMI, T2D and nephrolithiasis showed causal effects. Comprehensive follow-up analyses suggested that: (1) increased hypertension is a risk factor for CKD in Europeans but not in East Asians, suggesting the possibility of ancestry-specific disease aetiology; (2) T2D may have glucose-independent mechanisms to influence CKD; (3) non-linear MR indicated BMI above 25 kg/m2 as a threshold for increasing CKD risk.

Conclusion: This study built up a strong causal link between cardiometabolic risk factors and CKD in two ancestries. This evidence could inform the design of future interventions to reduce the burden of CKD and its cardiometabolic co-morbidities.

Funding: J.Z. is funded by a Vice-Chancellor Fellowship from the University of Bristol. This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/1, MC_UU_00011/4 and MC_UU_00011/7). Jie Zheng is supported by the Academy of Medical Sciences (AMS) Springboard Award, the Wellcome Trust, the Government Department of Business, Energy and Industrial Strategy (BEIS), the British Heart Foundation and Diabetes UK (SBF006\1117). JZ is funded by the Vice-Chancellor Fellowship from the University of Bristol. This study was funded/supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (GDS, TRG and REW). This study received funding from the UK Medical Research Council (MR/R013942/1). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. J.Z., Y.M.Z. and T.R.G are funded by a BBSRC Innovation fellowship. Y.M.Z. is supported by the National Natural Science Foundation of China (81800636). H.Z. is supported by the Training Program of the Major Research Plan of the National Natural Science Foundation of China (91642120), the Grant from the Science and Technology Project of Beijing, China (D18110700010000) and the University of Michigan Health System–Peking University Health Science Center Joint Institute for Translational and Clinical Research (BMU2017JI007). N.F. is supported by the National Institutes of Health awards R01-MD012765, R01- DK117445 and R21-HL140385. R.C. is funded by a Wellcome Trust GW4 Clinical Academic Training Fellowship (WT 212557/Z/18/Z). The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. M.C.B. is supported by the UK Medical Research Council (MRC) Skills Development Fellowship (MR/P014054/1). S.F. is supported by a Wellcome Trust PhD studentship (WT108902/Z/15/Z). Q.Y. is funded by a China Scholarship Council PhD scholarship (CSC201808060273). Y.C. was supported by the National Key R&D Program of China (2016YFC0900500, 2016YFC0900501, 2016YFC0900504). The China Kadoorie Biobank baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z). Japan-Kidney-Biobank was supported by AMED under Grant Number 20km0405210. P.C.H. is supported by Cancer Research UK [grant number: C18281/A19169]. A.K. was supported by DFG KO 3598/5-1. N.F. is supported by NIH awards R01-DK117445, R01-MD012765, R21- HL140385.

Declaration of Interest: T.R.G. and J.Z. receive funding from GlaxoSmithKline and Biogen for unrelated research. All other authors have nothing to declare.

Ethical Approval: All participants included in the CKDGen, UK Biobank, HUNT, Biobank Japan, China Kadoorie Biobank and Japan Kidney Biobank/ToMMo provided written informed consent and studies were approved by their local research ethics committees and institutional review boards as applicable.

Suggested Citation

Zheng, Jie and Zhang, Yue-Miao and Rasheed, Humaira and Walker, Venexia and Sugawara, Yuka and Li, JiaChen and Leng, Yue and Elsworth, Benjamin and Wootton, Robyn E. and Fang, Si and Yang, Qian and Burgess, Stephen and Haycock, Philip C. and Borges, Maria Carolina and Cho, Yoonsu and Carnegie, Rebecca and Howell, Amy and Robinson, Jamie and Thomas, Laurent F. and Brumpton, Ben Michael and Hveem, Kristian and Hallan, Stein and Franceschini, Nora and Morris, Andrew P. and Köttgen, Anna and Pattaro, Cristian and Wuttke, Matthias and Yamamoto, Masayuki and Kashihara, Naoki and Akiyama, Masato and Kanai, Masahiro and Matsuda, Koichi and Kamatani, Yoichiro and Okada, Yukinori and Walters, Robin and Millwood, Iona Y. and Chen, Zhengming and Davey Smith, George and Barbour, Sean and Yu, Canqing and Åsvold, Bjørn Olav and Zhang, Hong and Gaunt, Tom R., Trans-Ethnic Mendelian Randomization Study Reveals Causal Relationships Between Cardiometabolic Factors and Chronic Kidney Disease. Available at SSRN: https://ssrn.com/abstract=3861555 or http://dx.doi.org/10.2139/ssrn.3861555

Jie Zheng

University of Bristol - Medical Research Council Integrative Epidemiology Unit

Bristol
United Kingdom

Yue-Miao Zhang (Contact Author)

Peking University - Key Laboratory of Renal Disease ( email )

Beijing
China

Humaira Rasheed

University of Bristol - Medical Research Council Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Venexia Walker

University of Bristol - Medical Research Council Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Yuka Sugawara

University of Tokyo Hospital - Division of Nephrology and Endocrinology ( email )

Tokyo
Japan

JiaChen Li

Peking University - Department of Epidemiology and Biostatistics

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Yue Leng

University of California, San Francisco (UCSF) - Department of Psychiatry, Neurology and Epidemiology

982 Mission St
San Francisco, CA 94103
United States

Benjamin Elsworth

University of Bristol - MRC Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Robyn E. Wootton

University of Bristol - MRC Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Si Fang

University of Bristol - MRC Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Qian Yang

University of Bristol - Medical Research Council Integrative Epidemiology Unit

Bristol
United Kingdom

Stephen Burgess

University of Cambridge - MRC Biostatistics Unit

Cambridge, CB2 OSR
United Kingdom

Philip C. Haycock

University of Bristol - MRC Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Maria Carolina Borges

University of Bristol - MRC Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Yoonsu Cho

University of Bristol - MRC Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Rebecca Carnegie

University of Bristol - MRC Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Amy Howell

University of Bristol - Medical Research Council Integrative Epidemiology Unit

Bristol
United Kingdom

Jamie Robinson

University of Bristol - Medical Research Council Integrative Epidemiology Unit

Bristol
United Kingdom

Laurent F. Thomas

Norwegian University of Science and Technology (NTNU) - K.G. Jebsen Center for Genetic Epidemiology ( email )

Høgskoleringen
Trondheim NO-7491, 7491
Norway

Ben Michael Brumpton

University of Bristol - MRC Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Kristian Hveem

Norwegian University of Science and Technology (NTNU) - K.G. Jebsen Center for Genetic Epidemiology ( email )

Høgskoleringen
Trondheim NO-7491, 7491
Norway

Stein Hallan

Norwegian University of Science and Technology (NTNU) - Department of Clinical and Molecular Medicine ( email )

Høgskoleringen
Trondheim NO-7491, 7491
Norway

Nora Franceschini

University of North Carolina (UNC) at Chapel Hill - Department of Epidemiology ( email )

102 Ridge Road
Chapel Hill, NC NC 27514
United States

Andrew P. Morris

The University of Manchester

Booth St West
Manchester, M15 6PB
United Kingdom

Anna Köttgen

University of Freiburg - Institute of Genetic Epidemiology ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Cristian Pattaro

EURAC Research ( email )

Viale Druso, 1
Drususallee 1
Bolzano / Bozen, 39100
Italy

Matthias Wuttke

University of Freiburg - Institute of Genetic Epidemiology ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Masayuki Yamamoto

Tohoku University - Department of Medical Biochemistry ( email )

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Naoki Kashihara

Kawasaki Medical School - Department of Nephrology and Hypertension

Okayama 701-0192
Japan

Masato Akiyama

RIKEN Center for Integrative Medical Sciences - Laboratory for Statistical Analysis ( email )

1-7-22, Suehiro-cho
Tsurumi-ku
Yokohama, Kanagawa
Japan

Masahiro Kanai

Masssachusetts Institute of Technology and Harvard University - Broad Institute ( email )

415 Main Street
Cambridge, MA 02142
United States

Koichi Matsuda

University of Tokyo, Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences

Kashiwa, 277-8568
Japan

Yoichiro Kamatani

RIKEN Center for Integrative Medical Sciences ( email )

1-7-22, Suehiro-cho
Tsurumi-ku
Yokohama
Japan

Yukinori Okada

Osaka University - Department of Statistical Genetics

Osaka
Japan

Robin Walters

University of Oxford

Iona Y. Millwood

University of Oxford

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Zhengming Chen

University of Oxford - Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU)

Richard Doll Building
Old Road Campus
Oxford, OX3 7LF
United Kingdom

George Davey Smith

University of Bristol - MRC Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

Social Medicine, University of Bristol ( email )

Bristol
United Kingdom

Sean Barbour

University of British Columbia (UBC) - Division of Nephrology ( email )

2329 West Mall
Vancouver, British Columbia BC V6T 1Z4
Canada

University of British Columbia (UBC) - Division of Nephrology ( email )

2329 West Mall
Vancouver, British Columbia BC V6T 1Z4
Canada

Canqing Yu

Peking University Health Science Center - School of Public Health ( email )

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Bjørn Olav Åsvold

K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology ( email )

Trondheim
Norway

Hong Zhang

Peking University - Renal Division

Beijing
China

Tom R. Gaunt

University of Bristol - MRC Integrative Epidemiology Unit ( email )

Bristol
United Kingdom

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