Apolipoprotein A-IV

Members

Principal Investigator (PI)

Florian Kronenberg

Co-PI

Barbara Kollerits , Claudia Lamina , Hans Dieplinger

Team

Adriana Koller

About

There exists accumulating evidence from in vitro studies that apolipoprotein A-IV (apoA-IV) plays an important role in reverse cholesterol transport. Our group focuses on the following research issues related to apoA-IV.

ApoA-IV in patients with atherosclerotic complications

We demonstrated for the first time that decreased plasma concentrations of apoA-IV are associated with atherosclerotic complications. This association was observed in the general population (Figure 1) as well as in patients with chronic kidney disease.

Figure 1: ApoA-IV plasma concentrations in patients with coronary artery disease and healthy controls. Data are provided for a Caucasian as well as an Asian Indian group of patients and controls (Kronenberg et al.: J. Am. Coll. Cardiol. 2000).
Figure 1: ApoA-IV plasma concentrations in patients with coronary artery disease and healthy controls. Data are provided for a Caucasian as well as an Asian Indian group of patients and controls (Kronenberg et al.: J. Am. Coll. Cardiol. 2000).

ApoA-IV in patients with renal disease

In patients with renal disease we observed that apoA-IV concentrations start to increase during the earliest phases of renal impairment making apoA IV to an early marker of renal impairment (Figure 2).

Figure 2: Mean (± standard deviation) apolipoprotein A-IV (apoA-IV) concentrations and number of patients stratified by estimated glomerular filtration rate (eGFR) and urine albumin–creatinine ratio (UACR) risk categories (including nephrotic range albuminuria >2220 mg/g) according to KDIGO guidelines in the German Chronic Kidney Disease (GCKD) study (Schwaiger et al.: Clin. J. Am. Soc. Nephrol. 2022).
Figure 2: Mean (± standard deviation) apolipoprotein A-IV (apoA-IV) concentrations and number of patients stratified by estimated glomerular filtration rate (eGFR) and urine albumin–creatinine ratio (UACR) risk categories (including nephrotic range albuminuria >2220 mg/g) according to KDIGO guidelines in the German Chronic Kidney Disease (GCKD) study (Schwaiger et al.: Clin. J. Am. Soc. Nephrol. 2022).

Dialysis patients have twice as high plasma concentrations than healthy controls. In the “Mild to Moderate Kidney Disease Study” (MMKD) we found that the presence of high concentrations of apoA-IV is a reliable predictor for a progression of kidney disease during the following years of observation. This association was independent from the baseline glomerular filtration rate and proteinuria (Figure 3).

Figure 3: Results from the 'Mild to Moderate Kidney Disease' (MMKD) Study on progression of kidney disease. Kaplan-Meier curves of renal endpoints in patients with infra- and supramedian plasma apoA-IV concentrations (Boes et al.: J. Am. Soc. Nephrol. 2006).
Figure 3: Results from the 'Mild to Moderate Kidney Disease' (MMKD) Study on progression of kidney disease. Kaplan-Meier curves of renal endpoints in patients with infra- and supramedian plasma apoA-IV concentrations (Boes et al.: J. Am. Soc. Nephrol. 2006).

Genetic regulation of apoA-IV concentrations

We published the first genome-wide association study in 2016. We identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1. The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles (Figure 4). Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations.

Figure 4: Manhattan-plot for the meta-analysis on log-transformed apoA-IV values. Results are based on five discovery cohorts including 13813 individuals (Lamina et al.: Hum. Mol. Genet. 2016).
Figure 4: Manhattan-plot for the meta-analysis on log-transformed apoA-IV values. Results are based on five discovery cohorts including 13813 individuals (Lamina et al.: Hum. Mol. Genet. 2016).

Cooperations

GCKD study, KORA Study Group, SAPHIR Study, Bruneck Study, Utah Obesity Case-Control Study, CoLaus Study, Cardiovascular Risk in Young Finns Study, Rotterdam Study, CAVASIC Study

Earlier Team Members

Schwaiger Johannes, Salome Mack, Stephanie Stangl, Marina Haiman, Benjamin Ezeh, Evi Trenkwalder, Eva Boes, Arno Lingenhel, Doreen Dähnhardt

Publications

Schwaiger JP, Kollerits B, Steinbrenner I, Weissensteiner H, Schönherr S, Forer L, Kotsis F, Lamina C, Schneider MP, Schultheiss UT, Wanner C, Köttgen A, Eckardt KU, Kronenberg F, GCKD Investigators: Apolipoprotein A-IV concentrations and clinical outcomes in a large chronic kidney disease cohort: Results from the GCKD study. J. Intern. Med. 291:622-636, 2022. PMID: 34914850   Journal Article

Lamina C, Friedel S, Coassin S, Rueedi R, Yousri NA, Seppälä I, Gieger C, Schönherr S, Forer L, Erhart G, Kollerits B, Marques-Vidal P, Ried J, Waeber G, Bergmann S, Dähnhardt D, Stöckl A, Kiechl S, Raitakari OT, Kähönen M, Willeit J, Kedenko L, Paulweber B, Peters A, Meitinger T, Strauch K, KORA Study Group, Lehtimäki T, Hunt SC, Vollenweider P, Kronenberg F: A genome-wide association meta-analysis on apolipoprotein A-IV concentrations. Hum. Mol. Genet. 25:3635-3646, 2016. PMID: 27412012   Journal Article

Mack S, Coassin S, Vaucher J, Kronenberg F, Lamina C, ApoA-IV-GWAS Consortium: Evaluating the causal relation of ApoA-IV with disease-related traits - A bidirectional two-sample Mendelian randomization study. Sci. Rep. 7:8734, 2017. PMID: 28821713   Journal Article

Kronenberg F: Apolipoprotein L1 and apolipoprotein A-IV and their association with kidney function. Curr. Opin. Lipidol. 28:39-45, 2017. PMID: 27870653   Editorial

Stangl S, Kollerits B, Lamina C, Meisinger C, Huth C, Stöckl A, Dähnhardt D, Böger CA, Krämer BK, Peters A, Kronenberg F: Association between apolipoprotein A-IV concentrations and chronic kidney disease in two large population-based cohorts: results from the KORA studies. J. Intern. Med. 278:410-423, 2015. PMID: 26037138   Journal Article

Kollerits B, Krane V, Drechsler C, Lamina C, März W, Ritz E, Wanner C, Kronenberg F, German Diabetes and Dialysis Study Investigators: Apolipoprotein A-IV concentrations and clinical outcomes in haemodialysis patients with type 2 diabetes mellitus–a post hoc analysis of the 4D Study. J. Intern. Med. 272:592-600, 2012. PMID: 22891946   Journal Article

Kronenberg F: Emerging risk factors and markers of chronic kidney disease progression. Nat. Rev. Nephrol. 5:677-689, 2009. PMID: 19935815   Review

Lingenhel A, Lhotta K, Neyer U, Heid IM, Rantner B, Kronenberg MF, König P, von Eckardstein A, Schober M, Dieplinger H, Kronenberg F: Role of the kidney in the metabolism of apolipoprotein A-IV: influence of the type of proteinuria. J. Lipid Res. 47:2071-2079, 2006. PMID: 16788210   Journal Article

Boes E, Fliser D, Ritz E, König P, Lhotta K, Mann JF, Müller GA, Neyer U, Riegel W, Riegler P, Kronenberg F: Apolipoprotein A-IV predicts progression of chronic kidney disease: the mild to moderate kidney disease study. J. Am. Soc. Nephrol. 17:528-536, 2006. PMID: 16382017   Journal Article

Haiman M, Salvenmoser W, Scheiber K, Lingenhel A, Rudolph C, Schmitz G, Kronenberg F, Dieplinger H: Immunohistochemical localization of apolipoprotein A-IV in human kidney tissue. Kidney Int. 68:1130-1136, 2005. PMID: 16105043   Journal Article