Metabolomics profiling in multi-ancestral individuals with type 2 diabetes in Singapore identified metabolites associated with renal function decline

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发表日期：

2024年12月2日

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Yuqing Chen,
Federico Torta,
Hiromi W. L. Koh,
Peter I. Benke,
Resham L. Gurung,
Jian-Jun Liu,
Keven Ang,
Yi-Ming Shao,
Gek Cher Chan,
Jason Chon-Jun Choo,
Jianhong Ching,
Jean-Paul Kovalik,
Tosha Kalhan,
Rajkumar Dorajoo,
Chiea Chuen Khor,
Yun Li,
Wern Ee Tang,
Darren E. J. Seah,
Charumathi Sabanayagam,
Radoslaw M. Sobota,
Kavita Venkataraman,
Thomas Coffman,
Markus R. Wenk,
Xueling Sim,
Su-Chi Lim,
E Shyong Tai

摘要

Aims/hypothesis

This study aims to explore the association between plasma metabolites and chronic kidney disease progression in individuals with type 2 diabetes.

Methods

We performed a comprehensive metabolomic analysis in a prospective cohort study of 5144 multi-ancestral individuals with type 2 diabetes in Singapore, using eGFR slope as the primary outcome of kidney function decline. In addition, we performed genome-wide association studies on metabolites to assess how these metabolites could be genetically influenced by metabolite quantitative trait loci and performed colocalisation analysis to identify genes affecting both metabolites and kidney function.

Results

Elevated levels of 61 lipids with long unsaturated fatty acid chains such as phosphatidylethanolamines, triacylglycerols, diacylglycerols, ceramides and deoxysphingolipids were prospectively associated with more rapid kidney function decline. In addition, elevated levels of seven amino acids and three lipids in the plasma were associated with a slower decline in eGFR. We also identified 15 metabolite quantitative trait loci associated with these metabolites, within which variants near TM6SF2, APOE and CPS1 could affect both metabolite levels and kidney functions.

Conclusions/interpretation

Our study identified plasma metabolites associated with prospective renal function decline, offering insights into the underlying mechanism by which the metabolite abnormalities due to fatty acid oversupply might reflect impaired β-oxidation and associate with future chronic kidney disease progression in individuals with diabetes.

Graphical Abstract