Afamin

Members

Principal Investigator (PI)

Florian Kronenberg , Hans Dieplinger

Co-PI

Barbara Kollerits , Claudia Lamina

Team

Bernhard Rupp

Association of afamin with metabolic syndrome and diabetes mellitus

On the basis of results of a study in transgenic mice overexpressing the human plasma protein afamin and revealing a metabolic-syndrome-like phenotype, we investigated a possible association between afamin concentrations and metabolic syndrome in three independent, population-based cohorts comprising >5000 participants of European ancestry. Plasma afamin concentrations were found to be consistently associated with both the prevalence and the incidence of metabolic syndrome (Figure 1). In particular, the association between afamin levels and metabolic syndrome was observed for all components of the syndrome. In a further study we investigated whether afamin concentrations are associated with prediabetes, type 2 diabetes, and insulin resistance. In a pooled analysis in >20,000 individuals we showed that afamin is strongly associated with insulin resistance, prevalence, and incidence of type 2 diabetes independent of major metabolic risk factors or parameters. We concluded that afamin might be a promising novel marker for the identification of individuals at high risk for the development of type 2 diabetes.

Figure 1: Association between unadjusted mean plasma afamin concentrations (95% confidence interval) and number of metabolic syndrome components at baseline in the Bruneck study (n=826), SAPHIR study (n=1499), and KORA F4 study (n=3060). n represents the number of participants with the respective number of metabolic syndrome components in each of the studies. (Kronenberg et al. 2014).
Figure 1: Association between unadjusted mean plasma afamin concentrations (95% confidence interval) and number of metabolic syndrome components at baseline in the Bruneck study (n=826), SAPHIR study (n=1499), and KORA F4 study (n=3060). n represents the number of participants with the respective number of metabolic syndrome components in each of the studies. (Kronenberg et al. 2014).
Figure 2: Association between mean plasma afamin concentrations (95% confidence interval) measured at baseline and the change in number of metabolic syndrome components between baseline and follow-up investigation 5 years later in the Bruneck and the SAPHIR study populations. Data were adjusted for metabolic syndrome components at baseline. n provides the number of participants with the respective change in number of metabolic syndrome components during the observation period for each of the 2 studies. (Kronenberg et al. 2014).
Figure 2: Association between mean plasma afamin concentrations (95% confidence interval) measured at baseline and the change in number of metabolic syndrome components between baseline and follow-up investigation 5 years later in the Bruneck and the SAPHIR study populations. Data were adjusted for metabolic syndrome components at baseline. n provides the number of participants with the respective change in number of metabolic syndrome components during the observation period for each of the 2 studies. (Kronenberg et al. 2014).
Figure 3: Forest plot illustrating the association of an afamin increment of 10 mg/L with prevalent type 2 diabetes for eight studies as well as excluding the KORA F3 Study and NPHS-II since most participants in these studies were nonfasting. (Kollerits et al. 2017).
Figure 3: Forest plot illustrating the association of an afamin increment of 10 mg/L with prevalent type 2 diabetes for eight studies as well as excluding the KORA F3 Study and NPHS-II since most participants in these studies were nonfasting. (Kollerits et al. 2017).
Figure 4: Forest plot illustrating the association of a 10 mg/L increment of afamin with incident type 2 diabetes for all eight studies as well as excluding the KORA F3 Study and NPHS-II. (Kollerits et al. 2017)
Figure 4: Forest plot illustrating the association of a 10 mg/L increment of afamin with incident type 2 diabetes for all eight studies as well as excluding the KORA F3 Study and NPHS-II. (Kollerits et al. 2017)

Further studies showed a pronounced association with non-alcoholic fatty liver disease and increased hepatic fat content.

Association of serum afamin concentrations with kidney failure in chronic kidney disease patients: findings from the prospective GCKD cohort study

In the first prospective study in more than 5,000 patients with CKD (GCKD study), we found a highly significant association between serum afamin concentrations with parameters of kidney function and a lower risk of future kidney failure. Thus, afamin might reflect aspects of kidney function other than changes in the filtration barrier.

Figure 5: Graphical Abstract (Kollerits et.al. Am J. Kidney Dis. 2025).
Figure 5: Graphical Abstract (Kollerits et.al. Am J. Kidney Dis. 2025).
Figure 6: Mean (±SD) afamin concentrations and number of patients stratified by estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) risk categories (including nephrotic range UACR >2220 mg/g) according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines in the German Chronic Kidney Disease (GCKD) study. Mean afamin concentrations were higher in individuals with better kidney function (higher eGFR and lower UACR). Increasing concentrations of afamin are displayed with cell backgrounds with lighter blue background colors (change in color per 2mg/L increment of afamin concentrations). Note: numbers of patients do not add up to the total number from GCKD with available afamin values due to missing values for eGFR and UACR (Kollerits et.al. Am J. Kidney Dis. 2025).
Figure 6: Mean (±SD) afamin concentrations and number of patients stratified by estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) risk categories (including nephrotic range UACR >2220 mg/g) according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines in the German Chronic Kidney Disease (GCKD) study. Mean afamin concentrations were higher in individuals with better kidney function (higher eGFR and lower UACR). Increasing concentrations of afamin are displayed with cell backgrounds with lighter blue background colors (change in color per 2mg/L increment of afamin concentrations). Note: numbers of patients do not add up to the total number from GCKD with available afamin values due to missing values for eGFR and UACR (Kollerits et.al. Am J. Kidney Dis. 2025).

Earlier studies on Afamin by Hans Dieplinger and colleagues

These studies employed cell culture, animal model, biochemical-functional and clinical-epidemiological approaches to examine afamin’s possible function in fertility, neuroprotection, cancer and cardiovascular diseases.

Cooperations

GCKD study, KORA Study Group, SAPHIR Study, Bruneck Study, NHLBI Family Heart Study, CoLaus Study, Second Northwick Park Heart Study, Cardiovascular Risk in Young Finns Study

Earlier Team Members

Lidija Jerkovic, Andreas Vögele, Andreas Melmer, Benjamin Dieplinger, Andreas Naschberger, Allessandra Tramontana

Publications

Kollerits B, Kotsis F, Schneider MP, Schultheiss UT, Weissensteiner H, Schönherr S, Forer L, Meiselbach H, Wanner C, Eckardt KU, Dieplinger H, Kronenberg F, GCKD Investigators: Association of serum afamin concentrations with kidney failure in patients with CKD: Findings from the German CKD cohort study. Am. J. Kidney Dis. 85:432-441.e1, 2025. PMID: 39743167   Journal Article

Kronenberg F, Kollerits B, Kiechl S, Lamina C, Kedenko L, Meisinger C, Willeit J, Huth C, Wietzorrek G, Altmann ME, Thorand B, Melmer A, Dähnhardt D, Santer P, Rathmann W, Paulweber B, Koenig W, Peters A, Adham IM, Dieplinger H: Plasma concentrations of afamin are associated with the prevalence and development of metabolic syndrome. Circ. Cardiovasc. Genet. 7:822-829, 2014. PMID: 25176938   Journal Article

Kollerits B, Lamina C, Huth C, Marques-Vidal P, Kiechl S, Seppälä I, Cooper J, Hunt SC, Meisinger C, Herder C, Kedenko L, Willeit J, Thorand B, Dähnhardt D, Stöckl D, Willeit K, Roden M, Rathmann W, Paulweber B, Peters A, Kähönen M, Lehtimäki T, Raitakari OT, Humphries SE, Vollenweider P, Dieplinger H, Kronenberg F: Plasma concentrations of afamin are associated with prevalent and incident type 2 diabetes: A pooled analysis in more than 20,000 individuals. Diabetes Care 40:1386-1393, 2017. PMID: 28877915   Journal Article

Pitkänen N, Finkenstedt A, Lamina C, Juonala M, Kähönen M, Mäkelä KM, Dieplinger B, Viveiros A, Melmer A, Leitner I, Kedenko L, Seppälä I, Viikari JSA, Mueller T, Kronenberg F, Paulweber B, Lehtimäki T, Zoller H, Raitakari OT, Dieplinger H: Afamin predicts the prevalence and incidence of nonalcoholic fatty liver disease. Clin. Chem. Lab. Med. 60:243-251, 2022. PMID: 34850615   Journal Article

Kurdiova T, Balaz M, Kovanicova Z, Zemkova E, Kuzma M, Belan V, Payer J, Gasperikova D, Dieplinger H, Ukropcova B, Ukropec J: Serum afamin a novel marker of increased hepatic lipid content. Front. Endocrinol. (Lausanne) 12:670425, 2021. PMID: 34603196   Journal Article

Köninger A, Iannaccone A, Hajder E, Frank M, Schmidt B, Schleussner E, Kimmig R, Gellhaus A, Dieplinger H: Afamin predicts gestational diabetes in polycystic ovary syndrome patients preconceptionally. Endocr. Connect. 8:616-624, 2019. PMID: 30991357   Journal Article

Köninger A, Enekwe A, Mach P, Andrikos D, Schmidt B, Frank M, Birdir C, Kimmig R, Gellhaus A, Dieplinger H: Afamin: an early predictor of preeclampsia. Arch. Gynecol. Obstet. 298:1009-1016, 2018. PMID: 30220025   Journal Article

Köninger A, Mathan A, Mach P, Frank M, Schmidt B, Schleussner E, Kimmig R, Gellhaus A, Dieplinger H: Is Afamin a novel biomarker for gestational diabetes mellitus? A pilot study. Reprod. Biol. Endocrinol. 16:30, 2018. PMID: 29587878   Journal Article

Altamirano A, Naschberger A, Fürnrohr BG, Saldova R, Struwe WB, Jennings PM, Millán Martín S, Malic S, Plangger I, Lechner S, Pisano R, Peretti N, Linke B, Aguiar MM, Fresser F, Ritsch A, Lenac Rovis T, Goode C, Rudd PM, Scheffzek K, Rupp B, Dieplinger H: Expression, purification, and biochemical characterization of human afamin. J. Proteome Res. 17:1269-1277, 2018. PMID: 29441788   Journal Article

Tramontana A, Pablik E, Stangl G, Hartmann B, Dieplinger H, Hafner E: Combination of first trimester serum afamin levels and three-dimensional placental bed vascularization as a possible screening method to detect women at-risk for adverse pregnancy complications like pre-eclampsia and gestational diabetes mellitus in low-risk pregnancies. Placenta 62:Sep.15, 2018. PMID: 29405972   Journal Article

Tramontana A, Dieplinger B, Stangl G, Hafner E, Dieplinger H: First trimester serum afamin concentrations are associated with the development of pre-eclampsia and gestational diabetes mellitus in pregnant women. Clin. Chim. Acta 476:160-166, 2018. PMID: 29191735   Journal Article

Naschberger A, Orry A, Lechner S, Bowler MW, Nurizzo D, Novokmet M, Keller MA, Oemer G, Seppi D, Haslbeck M, Pansi K, Dieplinger H, Rupp B: Structural evidence for a role of the multi-functional human glycoprotein afamin in Wnt transport. Structure 25:1907-1915.e5, 2017. PMID: 29153507   Journal Article

Naschberger A, Fürnrohr BG, Lenac Rovis T, Malic S, Scheffzek K, Dieplinger H, Rupp B: The N14 anti-afamin antibody Fab: a rare VL1 CDR glycosylation, crystallographic re-sequencing, molecular plasticity and conservative versus enthusiastic modelling. Acta Crystallogr. D Struct. Biol. 72:1267-1280, 2016. PMID: 27917827   Journal Article

Dieplinger H, Dieplinger B: Afamin–A pleiotropic glycoprotein involved in various disease states. Clin. Chim. Acta 446:105-110, 2015. PMID: 25892677   Review

Seeber B, Morandell E, Lunger F, Wildt L, Dieplinger H: Afamin serum concentrations are associated with insulin resistance and metabolic syndrome in polycystic ovary syndrome. Reprod. Biol. Endocrinol. 12:88, 2014. PMID: 25208973   Journal Article

Köninger A, Edimiris P, Koch L, Enekwe A, Lamina C, Kasimir-Bauer S, Kimmig R, Dieplinger H: Serum concentrations of afamin are elevated in patients with polycystic ovary syndrome. Endocr. Connect. 3:120-126, 2014. PMID: 24928911   Journal Article

Hubalek M, Buchner H, Mörtl MG, Schlembach D, Huppertz B, Firulovic B, Köhler W, Hafner E, Dieplinger B, Wildt L, Dieplinger H: The vitamin E-binding protein afamin increases in maternal serum during pregnancy. Clin. Chim. Acta 434:41-47, 2014. PMID: 24768783   Journal Article

Dieplinger B, Egger M, Gabriel C, Poelz W, Morandell E, Seeber B, Kronenberg F, Haltmayer M, Mueller T, Dieplinger H: Analytical characterization and clinical evaluation of an enzyme-linked immunosorbent assay for measurement of afamin in human plasma. Clin. Chim. Acta 425:236-241, 2013. PMID: 23981841   Journal Article

Melmer A, Fineder L, Lamina C, Kollerits B, Dieplinger B, Braicu I, Sehouli J, Cadron I, Vergote I, Mahner S, Zeimet AG, Castillo-Tong DC, Ebenbichler CF, Zeillinger R, Dieplinger H: Plasma concentrations of the vitamin E-binding protein afamin are associated with overall and progression-free survival and platinum sensitivity in serous ovarian cancer–a study by the OVCAD consortium. Gynecol. Oncol. 128:38-43, 2013. PMID: 23063758   Journal Article

Seeber BE, Czech T, Buchner H, Barnhart KT, Seger C, Daxenbichler G, Wildt L, Dieplinger H: The vitamin E-binding protein afamin is altered significantly in the peritoneal fluid of women with endometriosis. Fertil. Steril. 94:2923-2926, 2010. PMID: 20858448   Journal Article

Dieplinger H, Ankerst DP, Burges A, Lenhard M, Lingenhel A, Fineder L, Buchner H, Stieber P: Afamin and apolipoprotein A-IV: novel protein markers for ovarian cancer. Cancer Epidemiol. Biomarkers Prev. 18:1127-1133, 2009. PMID: 19336561   Journal Article

Kratzer I, Bernhart E, Wintersperger A, Hammer A, Waltl S, Malle E, Sperk G, Wietzorrek G, Dieplinger H, Sattler W: Afamin is synthesized by cerebrovascular endothelial cells and mediates alpha-tocopherol transport across an in vitro model of the blood-brain barrier. J. Neurochem. 108:707-718, 2009. PMID: 19046407   Journal Article

Jackson D, Craven RA, Hutson RC, Graze I, Lueth P, Tonge RP, Hartley JL, Nickson JA, Rayner SJ, Johnston C, Dieplinger B, Hubalek M, Wilkinson N, Perren TJ, Kehoe S, Hall GD, Daxenbichler G, Dieplinger H, Selby PJ, Banks RE: Proteomic profiling identifies afamin as a potential biomarker for ovarian cancer. Clin. Cancer Res. 13:7370-7379, 2007. PMID: 18094419   Journal Article

Jerkovic L, Voegele AF, Chwatal S, Kronenberg F, Radcliffe CM, Wormald MR, Lobentanz EM, Ezeh B, Eller P, Dejori N, Dieplinger B, Lottspeich F, Sattler W, Uhr M, Mechtler K, Dwek RA, Rudd PM, Baier G, Dieplinger H: Afamin is a novel human vitamin E-binding glycoprotein characterization and in vitro expression. J. Proteome Res. 4:889-899, 2005. PMID: 15952736   Journal Article