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

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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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 (MR). 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 (eGFR) < 60 ml/min/1.73m2. 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 glycemic phenotypes on CKD were weak. Non-linear MR indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI above 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.
Original languageEnglish
Pages (from-to)1995-2010
Number of pages16
JournalInternational Journal of Epidemiology
Issue number6
Early online date20 Oct 2021
Publication statusPublished - 1 Dec 2021


  • chronic kidney disease
  • cardiometabolic risk factors
  • Mendelian randomization
  • causality
  • trans-ethnic study


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