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

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...

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Veröffentlicht in:PLoS genetics Jg. 18; H. 4; S. e1010139
Hauptverfasser: Cheng, Yurong, Li, Yong, Scherer, Nora, Grundner-Culemann, Franziska, Lehtimäki, Terho, Mishra, Binisha H., Raitakari, Olli T., Nauck, Matthias, Eckardt, Kai-Uwe, Sekula, Peggy, Schultheiss, Ulla T.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Public Library of Science 06.04.2022
Public Library of Science (PLoS)
Schlagworte:
Animal models
Animals
Biology and Life Sciences
Blood coagulation
Blood pressure
Cardiovascular diseases
Chromosomes
Creatinine
Creatinine - metabolism
Development and progression
Epidermal growth factor receptors
Female
Fibrosis
Gene expression
Gene frequency
Gene mapping
Genetic aspects
Genetics
Genome-wide association studies
Genome-Wide Association Study
Genomes
Glomerular filtration rate
Glycoproteins
Health aspects
Humans
Kallikrein
Kallikreins - genetics
Kidney diseases
Kidneys
Male
Medicine and Health Sciences
mRNA
Osteopontin
Osteopontin - genetics
Osteopontin - metabolism
Peptide mapping
Phenotypes
Physiology
Plasma proteins
Population
Population studies
Post-translation
Proteins
Proteinuria
Regions
Renal Insufficiency, Chronic - epidemiology
Renal Insufficiency, Chronic - genetics
Thrombosis
Germany
ISSN:1553-7404, 1553-7390, 1553-7404
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Zusammenfassung: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/1.73m 2 (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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a list of investigators participating in the GCKD Study can be found in S1 Information
The authors have declared that no competing interests exist.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1010139