Contributions of obesity to kidney health and disease – insights from Mendelian randomisation and the human kidney transcriptomics

Xiaoguang Xu, James Eales, Xiao Jiang, Eleanor Sanderson, Maciej Drzal, Sushant Saluja, David Scannali, Bryan Williams, Andrew Morris, Tomasz J. Guzik, Fadi J. Charchar, Michael V. Holmes, Maciej Tomaszewski

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney.
Methods and results: We performed observational, one-sample, two-sample Mendelian randomisation (MR) and multivariable MR studies in approximately 300,000 participants of white-British ancestry from UK Biobank and participants of predominantly European ancestry from genome-wide association studies. The MR analyses revealed that increasing values of genetically predicted body mass index (BMI) and waist circumference (WC) were causally associated with biochemical indices of renal function, kidney health index (a composite renal outcome derived from blood biochemistry, urine analysis, and International Classification of Disease-based kidney disease diagnoses) and both acute and chronic kidney diseases of different aetiologies including hypertensive renal disease and diabetic nephropathy. Approximately 13-16% and 21-26% of the potentially causal effect of obesity indices on kidney health were mediated by blood pressure and type 2 diabetes, respectively. A total of 61 pathways mapping primarily onto transcriptional/translational regulation, innate and adaptive immunity, extracellular matrix and metabolism were associated with obesity measures in gene set enrichment analysis in up to 467 kidney transcriptomes.
Conclusions: Our data show that a putatively causal association of obesity with renal health is largely independent of blood pressure and type 2 diabetes and uncover the signatures of obesity on the transcriptome of human kidney.
Translational Perspective: These findings indicate that obesity is causally linked to indices of renal health and the risk of different kidney diseases. This evidence substantiates the value of weight loss as a strategy of preventing and/or counteracting a decline in kidney health as well as decreasing the risk of renal disease.
Original languageEnglish
JournalCardiovascular research
Publication statusAccepted/In press - 3 Nov 2021

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