Contributions of obesity to kidney health and disease: insights from Mendelian randomization and the human kidney transcriptomics

Xiaoguang Xu, James M Eales, Xiao Jiang, Eleanor Sanderson, Maciej Drzal, Sushant Saluja, David Scannali, Bryan Williams, Andrew P Morris, Tomasz J Guzik, Fadi J Charchar, Michael V Holmes, Maciej Tomaszewski, Charalambos Antoniades (Editor)

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 randomization (MR) and multivariable MR studies in ∼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 and waist circumference 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, and 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.
Original languageEnglish
Article numbercvab357
Pages (from-to)3151-3161
Number of pages11
JournalCardiovascular research
Volume118
Issue number15
Early online date10 Dec 2021
DOIs
Publication statusPublished - 9 Dec 2022

Keywords

  • Kidney disease
  • Kidney function
  • Kidney transcriptome
  • Mendelian randomization
  • Obesity

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