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/1.73m 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.

Author summary

Osteopontin (OPN) is involved in many (patho)physiological processes of the human body. Among others, it is known to be associated with adverse kidney outcomes. Since its genetic underpinnings are incompletely understood, we conducted a genome-wide association study of OPN in a European chronic kidney disease (CKD) population (N = 4,897). Of the three detected signals, two could be replicated within a population-based study of Finns. One locus is located upstream of SPP1 which encodes the OPN protein and is related to OPN production. This gene was also disclosed by an analysis of rare variants, all presumably effecting the gene product. Another locus maps into KLKB1 encoding prekallikrein (PK) that after processing to kallikrein (KAL) is implicated in blood pressure control and inflammation among others. Overall, our results highlight the multi-functional role of OPN and its possible pathological role in CKD. Further studies are needed to elucidate the complex role of OPN in humans.