Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease

Jie Zheng; Yuemiao Zhang; Humaira Rasheed; Venexia Walker; Yuka Sugawara; Jiachen Li; Yue Leng; Benjamin Elsworth; Robyn E Wootton; Si Fang; Qian Yang; Stephen Burgess; Philip C Haycock; Maria Carolina Borges; Yoonsu Cho; Rebecca Carnegie; Amy Howell; Jamie Robinson; Laurent F Thomas; Ben Michael Brumpton; Kristian Hveem; Stein Hallan; Nora Franceschini; Andrew P Morris; Anna Köttgen; Cristian Pattaro; Matthias Wuttke; Masayuki Yamamoto; Naoki Kashihara; Masato Akiyama; Masahiro Kanai; Koichi Matsuda; Yoichiro Kamatani; Yukinori Okada; Robin Walters; Iona Y Millwood; Zhengming Chen; George Davey Smith; Sean Barbour; Canqing Yu; Bjørn Olav Åsvold; Hong Zhang; Tom R Gaunt

doi:10.1093/ije/dyab203

Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease

Int J Epidemiol. 2022 Jan 6;50(6):1995-2010. doi: 10.1093/ije/dyab203. Epub 2021 Oct 20.

Authors

Jie Zheng¹, Yuemiao Zhang², Humaira Rasheed^{1

3}, Venexia Walker^{1

4}, Yuka Sugawara⁵, Jiachen Li⁶, Yue Leng⁷, Benjamin Elsworth¹, Robyn E Wootton¹, Si Fang¹, Qian Yang¹, Stephen Burgess^{8

9}, Philip C Haycock¹, Maria Carolina Borges¹, Yoonsu Cho¹, Rebecca Carnegie¹, Amy Howell¹, Jamie Robinson¹, Laurent F Thomas^{3

10}, Ben Michael Brumpton^{1

3

11}, Kristian Hveem³, Stein Hallan^{10

12}, Nora Franceschini¹³, Andrew P Morris¹⁴, Anna Köttgen¹⁵, Cristian Pattaro¹⁶, Matthias Wuttke¹⁵, Masayuki Yamamoto¹⁷, Naoki Kashihara¹⁸, Masato Akiyama^{19

20}, Masahiro Kanai^{21

22}, Koichi Matsuda²³, Yoichiro Kamatani^{19

24}, Yukinori Okada^{22

25

26}, Robin Walters²⁷, Iona Y Millwood²⁷, Zhengming Chen²⁷, George Davey Smith^{1

28}, Sean Barbour^{29

30}, Canqing Yu⁶, Bjørn Olav Åsvold^{3

31}, Hong Zhang², Tom R Gaunt^{1

28}

Affiliations

¹ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
² Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, P. R. China.
³ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
⁴ Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵ Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan.
⁶ Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, P. R. China.
⁷ Department of Psychiatry, University of California, San Francisco, CA, USA.
⁸ MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.
⁹ Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁰ Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
¹¹ Department of Thoracic Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹² Department of Nephrology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹³ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
¹⁴ Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK.
¹⁵ Institute of Genetic Epidemiology, Department of Biometry, Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.
¹⁶ Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck), Bolzano, Italy.
¹⁷ Tohoku Medical Megabank Organization and Tohoku University Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
¹⁸ Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan.
¹⁹ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²⁰ Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
²¹ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
²² Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
²³ Department of Computational Biology and Medical Sciences, Graduate school of Frontier Sciences, the University of Tokyo, Tokyo, Japan.
²⁴ Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, Japan.
²⁵ Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
²⁶ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.
²⁷ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
²⁸ NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, UK.
²⁹ Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
³⁰ British Columbia Provincial Renal Agency, Vancouver, British Columbia, Canada.
³¹ Department of Endocrinology, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Abstract

Background: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization.

Methods: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included.

Results: Eight risk factors showed reliable evidence of 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 Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2.

Conclusions: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.

Keywords: Mendelian randomization; cardiometabolic risk factors; causality; chronic kidney disease; trans-ethnic study.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cardiovascular Diseases*
Diabetes Mellitus, Type 2* / genetics
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis
Random Allocation
Renal Insufficiency, Chronic* / epidemiology
Renal Insufficiency, Chronic* / genetics

Abstract

Publication types

MeSH terms

Grants and funding