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.

Childhood body mass index trajectories and associations with adult-onset chronic kidney disease in Denmark: A population-based cohort study

“…Nonetheless, tracking of body size is not likely to entirely explain the association as children with severe obesity already display kidney abnormalities [ 7 ]. Additionally, a large mendelian randomization study found evidence for a causal relationship between adult BMI levels of overweight or obesity with CKD [ 8 ], supporting that the associations in our study reflect an effect of BMI.…”

“…The primary risk factors for CKD vary by country; however, diabetes and hypertension are among the established leading causes, particularly in high-income countries [2,4]. Additionally, increasing evidence supports that excess adult adiposity is a substantial and causal contributor to CKD risk [5][6][7][8]. Although overweight and obesity are closely related to both diabetes and hypertension, it is suggested that excess adiposity may have effects on CKD risks independent of these 2 major causes of CKD [9].…”

Educational Attainment and Ischemic Stroke: A Mendelian Randomization Study

“…Thus, MR studies using these individuals could have been biased by population stratification or different ancestries (Davies et al, 2019). In fact, Zheng et al found that hypertension could play different causal roles on chronic kidney disease across ancestries (Zheng et al, 2022). Fourth, the underlying mechanisms about the causal association between educational attainment and IS remain unclear.…”

Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases

“…Others have developed and applied trans-ancestry methods for genetic correlation 11 , polygenic risk score 12,13 and fine mapping 14,15 analyses. However, multi-ancestry causal inference using MR is still in its infancy 16 . One major issue restricting the development of multi-ancestry MR is the unbalanced representation of genome-wide association study (GWAS) samples across different ethnic groups, with one commentary reporting that across published GWAS, 78% of participants were of European ancestry 17 .…”