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Case Study

Genetic Studies of Paired Metabolomes Reveal Enzymatic and Transport Processes at the Interface of Plasma and Urine

Metabolites in bodily fluids reflect a person’s unique chemistry and physiology. Genetics, environment, health and disease state all contribute to a person’s metabolic profile.1

A study published in Nature Genetics used Metabolon’s untargeted Global Discovery Panel to analyze the blood plasma and urine metabolomes of over 5,000 participants from the German Chronic Kidney Disease (GCKD) study. Parallel genome-wide screens were used to uncover genetic associations in kidney function that would have been missed by looking at plasma alone.2

A recent study published in Nature Genetics used Metabolon’s untargeted Global Discovery Panel to analyze the blood plasma and urine metabolomes of over 5,000 participants from the German Chronic Kidney Disease (GCKD) study. Parallel genome-wide screens were used to uncover genetic associations in kidney function that would have been missed by looking at plasma alone2.

Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine

Characterizing Kidney Function Using Parallel Metabolomes

The kidneys play a crucial role in removing waste from the body while retaining essential molecules like amino acids and sugars. With many of their functions still unknown, hundreds of transport proteins and enzymes involved in this process form the dark matter of the kidney. In the past, discoveries about specific kidney proteins were made by studying human diseases caused by single gene mutations. For instance, the sodium-glucose transporter SGLT2 was discovered in a rare genetic disease called familial renal glucosuria.3 Today, SGLT2 is a target for therapies treating diabetes and chronic kidney disease.

However, not all mutations in transport proteins lead to obvious diseases—this is where the combination of metabolomics and genomics comes into play. Schlosser and colleagues used Metabolon’s untargeted Global Discovery Panel to analyze the levels of 1,296 metabolites in plasma and 1,399 metabolites in urine. Combined with a genome-wide association approach, this study revealed 677 genetic loci in plasma and 622 in urine associated with 760 metabolites.2 All participants in the study had chronic kidney disease (CKD); however, most genetic effects on urine metabolites in people with CKD are also present in healthy adults.4

When Two Metabolomes are Better than One

Combining metabolomics with genomics isn’t new; however, previous genomics-metabolomics studies have primarily focused on metabolites from a single compartment, either plasma or urine.1,4,5 Among metabolites examined in both plasma and urine, about half (49%) of significantly associated genomic loci were identified only in one compartment or the other, and almost 40% of significant associations with a metabolite would have been missed by only studying plasma.2 For example, AQP-7, an aquaporin protein that transports water and glycerol, is localized to the apical membrane in the proximal tubule of the kidney, where its activity affects metabolites in urine but not plasma. On the other hand, SLC13A3, a transport protein facing the plasma, exclusively influences its associated metabolites in the plasma. And still, other proteins like the bile acid transporter SLC10A2 have distinct effects on both sides of the kidney interface and show genetic associations with their corresponding metabolites in both plasma and urine.

Implications for Health

The metabolome has been considered an avenue to more sensitive and accurate views of health and disease, both in the kidney and elsewhere, based on blood or urine metabolites.2,6,7 This study identified two urine metabolites that could be linked to cardiometabolic disease. Galactosylglycerol and 1,6-anhydroglucose were linked to FUT2 mutations that are also associated with lipid metabolism disorders, hypertension, and gallstones. These findings invite future studies to validate these associations and advance precision medicine through metabolomics.2,6

References

1. Surendran P, Stewart ID, Au Yeung VPW, et al. Rare and common genetic determinants of metabolic individuality and their effects on human health. Nat Med. 2022;28(11):2321-2332. doi:10.1038/s41591-022-02046-0

2. Schlosser P, Scherer N, Grundner-Culemann F, et al. Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine. Nat Genet. 2023;55:995-1008. doi:10.1038/s41588-023-01409-8

3. Gyimesi G, Pujol-Giménez J, Kanai Y, Hediger MA. Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application. Pflugers Arch. 2020;472(9):1177-1206. doi:10.1007/s00424-020-02433-x

4. Schlosser P, Li Y, Sekula P, et al. Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans. Nat Genet. 2020;52(2):167-176. doi:10.1038/s41588-019-0567-8

5. Lotta LA, Pietzner M, Stewart ID, et al. A cross-platform approach identifies genetic regulators of human metabolism and health. Nat Genet. 2021;53(1):54-64. doi:10.1038/s41588-020-00751-5

6. Davies R. The metabolomic quest for a biomarker in chronic kidney disease. Clin Kidney J. 2018;11(5):694-703. doi:10.1093/ckj/sfy037

7. Aderemi AV, Ayeleso AO, Oyedapo OO, Mukwevho E. Metabolomics: a scoping review of its role as a tool for disease biomarker discovery in selected non-communicable diseases. Metabolites. 2021;11(7):418. doi:10.3390/metabo11070418

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