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

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.

Osteopontin as a Biomarker in Chronic Kidney Disease

“…The chromosome location of the OPN gene varies by species; for example, the gene in human, and mice is located on chromosomes 4, and 5, respectively [16]. A genome-wide association of a European CKD population revealed two replicated loci, one upstream of SPP1, and another mapping onto KLKB1 encoding pre-kallikrein, which is involved in blood pressure control, inflammation, cancer, and cardiovascular disease [12]. An important paralog of KLKB1 is F11, which is associated with OPN expression in several tissues.…”

“…Among all tissues, kidneys have the greatest OPN content [12]. In normal kidneys, OPN is mainly expressed in the loop of Henle and the distal nephron [13], but following kidney damage, its expression is upregulated in all tubular segments and in the glomeruli by as much as 18-fold [13].…”

Will osteopontin bridge the gap towards clinical application in chronic kidney disease?

“…Genetic studies may help discern whether lowering osteopontin levels is ‘causally related’ with the risk of kidney failure. Another study from the GCKD cohort identified two replicated polymorphisms that were associated with serum osteopontin levels: one close to the SPP1 gene, encoding osteopontin, and another one that mapped to the KLKB1 gene encoding prekallikrein, which is processed to kallikrein [ 12 ]. Kallikrein, in turn, has been implicated through the kinin-kallikrein system in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease.…”

Sex-Specific Effects of Short-Term Oral Administration of Food-Grade Titanium Dioxide Nanoparticles in the Liver and Kidneys of Adult Rats

“…Osteopontin (SPP1), which is overexpressed in various malignancies promoting proliferation, migration, and invasion, is normally expressed in the bile duct epithelium, and represents a suitable, early diagnostic marker for hepatocarcinoma [ 15 ]. In renal tissues, SPP1 has been correlated with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney diseases [ 16 ]. In the liver, vascular endothelial growth factor (VEGF) is the main regulator of angiogenesis, and its expression was correlated with bile duct growth [ 15 ].…”