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 BrumptonKristian 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

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1995-2010
Number of pages16
JournalInternational Journal of Epidemiology
Issue number6
Publication statusPublished - Dec 1 2021

All Science Journal Classification (ASJC) codes

  • Epidemiology


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