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

PLoS Genet. 2022 Apr 6;18(4):e1010139. doi: 10.1371/journal.pgen.1010139. eCollection 2022 Apr.

Abstract

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.

MeSH terms

  • Animals
  • Creatinine / metabolism
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Kallikreins / genetics
  • Male
  • Osteopontin / genetics
  • Osteopontin / metabolism
  • Renal Insufficiency, Chronic* / epidemiology
  • Renal Insufficiency, Chronic* / genetics

Substances

  • SPP1 protein, human
  • Osteopontin
  • Creatinine
  • Kallikreins

Grants and funding

The work of UTS was supported within the e:Med (https://www.sys-med.de/en/) junior consortium CKDNapp (https://ckdn.app/), which is funded by grants from the German Ministry of Education and Research (BMBF, grant number 01ZX1912B; https://www.gesundheitsforschung-bmbf.de/de/ckdnapp-entwicklung-der-chronic-kidney-disease-nephrologists-app-10066.php). The work of PS was partially funded by German Research Foundation (DFG) Project-ID 431984000 - SFB 1453. The GCKD study was funded by grants from the BMBF (grant number 01ER0804) and the KfH Foundation for Preventive Medicine (https://www.kfh-stiftung-praeventivmedizin.de/content/stiftung) and corporate sponsors. Genotyping and measurements of osteopontin were supported by Bayer Pharma AG (https://www.bayer.com/en/). The Young Finns Study has been financially supported by the Academy of Finland (https://www.aka.fi/en/): grants 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland (https://www.kela.fi/web/en/); Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001; https://www.vsshp.fi/en/tutkijoille/rahoitus/Pages/default.aspx); Juho Vainio Foundation (https://juhovainionsaatio.fi/en/juho-vainio-foundation/); Paavo Nurmi Foundation (https://www.paavonurmensaatio.fi/saatio_e3.htm); Finnish Foundation for Cardiovascular Research (https://www.sydantutkimussaatio.fi/en/foundation); Finnish Cultural Foundation (https://skr.fi/en); The Sigrid Juselius Foundation (https://www.sigridjuselius.fi/en/); Tampere Tuberculosis Foundation (http://www.tuberkuloosisaatio.fi/); Emil Aaltonen Foundation (https://emilaaltonen.fi/apurahat/in-english/); Yrjö Jahnsson Foundation (https://www.yjs.fi/en/); Signe and Ane Gyllenberg Foundation (https://gyllenbergs.fi/en/); Diabetes Research Foundation of Finnish Diabetes Association (https://www.diabetes.fi/en/finnish_diabetes_association/association/the_diabetes_research_foundation). This project has received funding from the European Union’s Horizon 2020 research and innovation programme (https://ec.europa.eu/programmes/horizon2020/en/home) under grant agreements No 848146 (To Aition) and No 755320 (TAXINOMISIS). This project has received funding from the European Research Council (ERC; https://erc.europa.eu/) advanced grants under grant agreement No 742927 (MULTIEPIGEN project); Tampere University Hospital Supporting Foundation (https://www.tays.fi/en-US/Research_and_development) and Finnish Society of Clinical Chemistry (https://www.ifcc.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge support by the Open Access Publication Fund of the University of Freiburg.