Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism

Cheng, Yu-Rong; Schlosser, Pascal; Hertel, Johannes; Sekula, Peggy; Oefner, Peter J.; Spiekerkoetter, Ute; Mielke, Johanna; Freitag, Daniel F.; Schmidts, Miriam; Kronenberg, Florian; Eckardt, Kai‐Uwe; Thiele, Ines; Li, Yong; Köttgen, Anna

doi:10.1038/s41467-020-20877-8

Cited by 26 publications

(23 citation statements)

References 81 publications

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“…The COBRA approach has been successfully applied to a variety of biomedical questions [17] , [18] , including host-pathogen interactions [19] . One of the advantages of metabolic reconstructions is that they can be tailored to a particular question or condition through the application of constraints [15] , which could, for example, be dietary availability [20] , [21] , [22] , gene defects [23] , [24] , or omics data [25] , [26] , [27] . Hence, one metabolic reconstruction can give rise to many condition-specific models.…”

Section: Introductionmentioning

confidence: 99%

Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication

Thiele

Fleming

2022

Computational and Structural Biotechnology Journal

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Section: Introductionmentioning

confidence: 99%

Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication

Thiele

Fleming

2022

Computational and Structural Biotechnology Journal

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“…Furthermore, genome-wide association studies of urinary metabolites have identified the association between common sequence variants within or close to the genes encoding enzymes and transport proteins that enrich the mitochondrial matrix—the subcellular compartment in which many detoxification reactions and fatty acid and amino acid metabolism occur—and kidney-related traits (i.e. urine albumin-to-creatinine ratio and estimated glomerular filtration rate [ 13 ]) or different disease states, including chronic kidney disease [ 14 ]. These large-scale and multi-omics approaches thus support the fundamental role of mitochondria in organizing cellular homeostasis and organismal physiology, and its contribution to disease risk within the population.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia

Luciani

Govers

Sorrentino

et al. 2021

Cell. Mol. Life Sci.

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Mitochondria—the intracellular powerhouse in which nutrients are converted into energy in the form of ATP or heat—are highly dynamic, double-membraned organelles that harness a plethora of cellular functions that sustain energy metabolism and homeostasis. Exciting new discoveries now indicate that the maintenance of this ever changing and functionally pleiotropic organelle is particularly relevant in terminally differentiated cells that are highly dependent on aerobic metabolism. Given the central role in maintaining metabolic and physiological homeostasis, dysregulation of the mitochondrial network might therefore confer a potentially devastating vulnerability to high-energy requiring cell types, contributing to a broad variety of hereditary and acquired diseases. In this Review, we highlight the biological functions of mitochondria-localized enzymes from the perspective of understanding—and potentially reversing—the pathophysiology of inherited disorders affecting the homeostasis of the mitochondrial network and cellular metabolism. Using methylmalonic acidemia as a paradigm of complex mitochondrial dysfunction, we discuss how mitochondrial directed-signaling circuitries govern the homeostasis and physiology of specialized cell types and how these may be disturbed in disease. This Review also provides a critical analysis of affected tissues, potential molecular mechanisms, and novel cellular and animal models of methylmalonic acidemia which are being used to develop new therapeutic options for this disease. These insights might ultimately lead to new therapeutics, not only for methylmalonic acidemia, but also for other currently intractable mitochondrial diseases, potentially transforming our ability to regulate homeostasis and health.

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“…Overall, 4,879 GCKD participants with complete data on genotyping (Exome chip), eGFR, UACR and log 2 (OPN) measurements were included in the analysis of aggregated rare variant testing ( S1 Fig ) . As previously described [ 106 ], two types of rare variant aggregation tests (burden test, sequence kernel association test [SKAT]) implemented in the R package seqMeta (v1.6.7, [ 107 ]) were conducted using exome chip data and log 2 (OPN) measurements (outcome). Per gene, variants with MAF <1% and having a major effect on the gene product (nonsynonymous, stop gain/loss, splicing; “qualifying variants”) as annotated by dbNSFP v.2.0 were aggregated [ 24 , 25 ].…”

Section: Methodsmentioning

confidence: 99%

Genetics of osteopontin in patients with chronic kidney disease: The German Chronic Kidney Disease study

et al. 2022

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Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology.

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Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism

Cited by 26 publications

References 81 publications

Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication

Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication

Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia

Genetics of osteopontin in patients with chronic kidney disease: The German Chronic Kidney Disease study

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