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

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.

Figure 1

Study design of the trans-ethnic Mendelian-randomization study of chronic kidney disease CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.

Figure 2

Forest plot for causal effects of the 45 risk factors on chronic kidney disease in Europeans and the 17 risk factors on chronic kidney disease in Eastern Asians. (A) Causal estimates using European data; (B) causal estimates using Eastern Asian data. For binary exposures, the effect reported on the x-axis is the odds ratio of chronic kidney disease per doubling in the odds of the exposure. For continuous exposure, the effect on the x-axis is the odds ratio of chronic kidney disease per 1 standard deviation change in the exposure. CKD, chronic kidney disease.

Figure 3

Forest plot for causal effects of four blood-pressure phenotypes on chronic kidney disease risk. The subplots represent Mendelian-randomization results of different blood-pressure phenotypes. CKD, chronic kidney disease.

Figure 4

Non-linear Mendelian randomization of body mass index on chronic kidney disease risk. The dose–response curve between body mass index and chronic kidney disease risk for (A) UK Biobank and (B) the HUNT Study. The gradient at each point of the curve is the localized average causal effect. Shaded areas represent 95% confidence intervals. CKD, chronic kidney disease.