Skip to main content
SpringerLink
Log in

Association of α2-HS glycoprotein (AHSG, fetuin-A) polymorphism with AHSG and phosphate serum levels

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Alpha2-HS glycoprotein (AHSG), also known as fetuin-A, is a plasma protein displaying high-affinity interaction with calcium phosphate, by which ectopic vascular calcification is prevented. This investigation has attempted to evaluate the relationship between AHSG polymorphism and serum levels of AHSG and calcium-related parameters. AHSG levels in unrelated individuals were measured by quantitative rocket immunoelectrophoresis and were 581±38, 542±31, and 494±23mg/l for three major genotypes of AHSG1 homozygotes (n=99), heterozygotes (n=55), and AHSG2 homozygotes (n=22), respectively (differences were significant: P<0.001). The circulating AHSG level was therefore influenced by the genetic polymorphism with the additive reduction in the AHSG2 allele. Statistical analysis of simple and multiple regression models revealed no associations between AHSG levels and serum values of total calcium, albumin-corrected total calcium, and ionized calcium. However, the AHSG levels demonstrated a significant negative correlation with free phosphate levels (P<0.001), indicating that AHSG is a novel determinant of serum phosphate. The AHSG polymorphism is attributable to the hereditary variation of AHSG and phosphate serum levels, which may affect skeletal development and chronic disorders such as vascular calcification.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Auberger P, Falquerho L, Contreres JO, Pages G, Le Cam G, Rossi B, Le Cam A (1989) Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity. Cell 58:631–640

    Article  CAS  PubMed  Google Scholar 

  • Banine F, Gangneux C, Mercier L, Le Cam A, Salier JP (2000) Positive and negative elements modulate the promoter of the human liver-specific α2-HS-glycoprotein gene. Eur J Biochem 267:1214–1222

    Article  CAS  PubMed  Google Scholar 

  • Butler SJ, Payne RB, Gunn IR, Burns J, Paterson CR (1984) Correlation between serum ionised calcium and serum albumin concentrations in two hospital populations. Br Med J 289:948–950

    CAS  Google Scholar 

  • Cole DE, Peltekova VD, Rubin LA, Hawker GA, Vieth R, Liew CC, Hwang DM, Evrovski J, Hendy GN (1999) A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations. Lancet 353:112–115

    Article  CAS  PubMed  Google Scholar 

  • Cox DW, Andrews BJ, Wills DE (1986) Genetic polymorphism of α2HS-glycoprotein. Am J Hum Genet 38:699–706

    CAS  PubMed  Google Scholar 

  • Denecke B, Graber S, Schafer C, Heiss A, Woltje M, Jahnen-Dechent W (2003) Tissue distribution and activity testing suggest a similar but not identical function of fetuin-B and fetuin-A. Biochem J 376:135–145

    Article  CAS  PubMed  Google Scholar 

  • Dickson IR, Gwilliam R, Arora M, Murphy S, Khaw KT, Phillips C, Lincoln P (1994) Lumbar vertebral and femoral neck bone mineral density are higher in postmenopausal women with the α2HS-glycoprotein 2 phenotype. Bone Miner 24:181–188

    CAS  PubMed  Google Scholar 

  • Eichner JE, Friedrich CA, Cauley JA, Kamboh MI, Gutai JP, Kuller LH, Ferrell RE (1990) Alpha 2-HS glycoprotein phenotypes and quantitative hormone and bone measures in postmenopausal women. Calcif Tissue Int 47:345–349

    CAS  PubMed  Google Scholar 

  • Gangneux C, Daveau M, Hiron M, Derambure C, Papaconstantinou J, Salier JP (2003) The inflammation-induced down-regulation of plasma fetuin-A (α2HS-glycoprotein) in liver results from the loss of interaction between long C/EBP isoforms at two neighbouring binding sites. Nucleic Acids Res 31:5957–5970

    Article  CAS  PubMed  Google Scholar 

  • Heiss A, DuChesne A, Denecke B, Grotzinger J, Yamamoto K, Renne T, Jahnen-Dechent W (2003) Structural basis of calcification inhibition by α2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem 278:13333–13341

    Article  CAS  PubMed  Google Scholar 

  • Kalabay L, Cseh K, Pajor A, Baranyi E, Csákány GM, Melczer Z, Speer G, Kovács M, Siller G, Karádi I, Winkler G (2002) Correlation of maternal serum fetuin/α2-HS-glycoprotein concentration with maternal insulin resistance and anthropometric parameters of neonates in normal pregnancy and gestational diabetes. Eur J Endocrinol 147:243–248

    CAS  PubMed  Google Scholar 

  • Kalousdian S, Fabsitz R, Havlik R, Christian J, Rosenman R (1987) Heritability of clinical chemistries in an older twin cohort: the NHLBI Twin Study. Genet Epidemiol 4:1–11

    Google Scholar 

  • Keeley FW, Sitarz EE (1985) Identification and quantitation of alpha2-HS glycoprotein in the mineralized matrix of calcified plaques of atherosclerotic human aorta. Atherosclerosis 55:63–69

    CAS  PubMed  Google Scholar 

  • Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Böhm R, Metzger T, Wanner C, Jahnen-Dechent W, Floege J (2003) Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361:827–833

    Article  CAS  PubMed  Google Scholar 

  • Lebreton JP, Joisel F, Raoult JP, Lannuzel B, Rogez JP, Humbert G (1979) Serum concentration of human alpha2 HS glycoprotein during the inflammatory process: evidence that alpha2 HS glycoprotein is a negative acute-phase reactant. J Clin Invest 64:1118–1129

    CAS  PubMed  Google Scholar 

  • Liu XH, Liu YJ, Jiang DK, Li YM, Li MX, Qin YJ, Jian WX, Zhou Q, Deng HW (2003) No evidence for linkage and/or association of human alpha2-HS glycoprotein gene with bone mineral density variation in Chinese nuclear families. Calcif Tissue Int 73:244–250

    Article  CAS  PubMed  Google Scholar 

  • Mathews ST, Singh GP, Ranalletta M, Cintron VJ, Qiang X, Goustin AS, Jen KL, Charron MJ, Jahnen-Dechent W, Grunberger G (2002a) Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene. Diabetes 51:2450–2458

    CAS  PubMed  Google Scholar 

  • Mathews ST, Deutsch DD, Iyer G, Hora N, Pati B, Marsh J, Grunberger G (2002b) Plasma α2-HS glycoprotein concentrations in patients with acute myocardial infarction quantified by a modified ELISA. Clin Chim Acta 319:27–34

    Article  CAS  PubMed  Google Scholar 

  • Nawratil P, Lenzen S, Kellermann J, Haupt H, Schinke T, Müller-Esterl W, Jahnen-Dechent W (1996) Limited proteolysis of human α2-HS glycoprotein/fetuin. Evidence that a chymotryptic activity can release the connecting peptide. J Biol Chem 271:31735–31741

    Article  CAS  PubMed  Google Scholar 

  • Olivier E, Soury E, Ruminy P, Husson A, Parmentier F, Daveau M, Salier JP (2000) Fetuin-B, a second member of the fetuin family in mammals. Biochem J 350:589–597

    Article  CAS  PubMed  Google Scholar 

  • Osawa M, Umetsu K, Ohki T, Nagasawa T, Suzuki T, Takeichi S (1997) Molecular evidence for human alpha2-HS glycoprotein (AHSG) polymorphism. Hum Genet 99:18–21

    Article  CAS  PubMed  Google Scholar 

  • Osawa M, Yuasa I, Kitano T, Henke J, Kaneko M, Udono T, Saitou N, Umetsu K (2001) Haplotype analysis of the human α2-HS glycoprotein (fetuin) gene. Ann Hum Genet 65:27–34

    Article  CAS  PubMed  Google Scholar 

  • Peacock M, Turner CH, Econs MJ, Foroud T (2002) Genetics of osteoporosis. Endocr Rev 23:303–326

    Article  CAS  PubMed  Google Scholar 

  • Price PA, Lim JE (2003) The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin–mineral complex. J Biol Chem 278:22144–22152

    Article  CAS  PubMed  Google Scholar 

  • Price PA, Thomas GR, Pardini AW, Figueira WF, Caputo JM, Williamson MK (2002) Discovery of a high molecular weight complex of calcium, phosphate, fetuin, and matrix gamma-carboxyglutamic acid protein in the serum of etidronate-treated rats. J Biol Chem 277:3926–3934

    Article  CAS  PubMed  Google Scholar 

  • Price PA, Williamson MK, Nguyen TM, Than TN (2004) Serum levels of the fetuin–mineral complex correlate with artery calcification in the rat. J Biol Chem 279:1594–1600

    Article  CAS  PubMed  Google Scholar 

  • Schäfer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, Müller-Esterl W, Schinke T, Jahnen-Dechent W (2003) The serum protein α2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 112:357–366

    Article  PubMed  Google Scholar 

  • Schinke T, Amendt C, Trindl A, Poschke O, Müller-Esterl W, Jahnen-Dechent W (1996) The serum protein α2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. A possible role in mineralization and calcium homeostasis. J Biol Chem 271:20789–20796

    Article  CAS  PubMed  Google Scholar 

  • Suzuki M, Shimokawa H, Takagi Y, Sasaki S (1994) Calcium-binding properties of fetuin in fetal bovine serum. J Exp Zool 270:501–507

    CAS  PubMed  Google Scholar 

  • Szweras M, Liu D, Partridge EA, Pawling J, Sukhu B, Clokie C, Jahnen-Dechent W, Tenenbaum HC, Swallow CJ, Grynpas MD, Dennis JW (2002) Alpha 2-HS glycoprotein/fetuin, a transforming growth factor-beta/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling. J Biol Chem 277:19991–19997

    Article  CAS  PubMed  Google Scholar 

  • Thode J, Juul-Jorgensen B, Bhatia HM, Kjaerulf-Nielsen M, Bartels PD, Fogh-Andersen N, Siggaard-Andersen O (1989) Comparison of serum total calcium, albumin-corrected total calcium, and ionized calcium in 1213 patients with suspected calcium disorders. Scand J Clin Lab Invest 49:217–223

    CAS  PubMed  Google Scholar 

  • Triffitt JT, Gebauer 1, Ashton BA, Owen ME, Reynolds JJ (1976) Origin of plasma α2HS-glycoprotein and its accumulation in bone. Nature 262:226–227

    CAS  PubMed  Google Scholar 

  • Wajih N, Borras T, Xue W, Hutson SM, Wallin R (2004) Processing and transport of matrix g-carboxyglutamic acid protein and bone morphogenetic protein-2 in cultured human vascular smooth muscle cells: evidence for an uptake mechanism for serum fetuin. J Biol Chem 279:43052–43060

    Article  CAS  PubMed  Google Scholar 

  • Zmuda JM, Eichner JE, Ferrell RE, Bauer DC, Kuller LH, Cauley JA (1998) Genetic variation in α2HS-glycoprotein is related to calcaneal broadband ultrasound attenuation in older women. Calcif Tissue Int 63:5–8

    Article  CAS  PubMed  Google Scholar 

  • Zmuda JM, Cauley JA, Ferrell RE (1999) Recent progress in understanding the genetic susceptibility to osteoporosis. Genet Epidemiol 16:356–367

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a grant from the Uehara Memorial Foundation, Tokyo, Japan.

Author information

Authors and Affiliations

  1. Department of Experimental and Forensic Pathology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan

    Motoki Osawa, Wei Tian, Hidekazu Horiuchi, Mika Kaneko & Kazuo Umetsu

Authors
  1. Motoki Osawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hidekazu Horiuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mika Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazuo Umetsu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Motoki Osawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Osawa, M., Tian, W., Horiuchi, H. et al. Association of α2-HS glycoprotein (AHSG, fetuin-A) polymorphism with AHSG and phosphate serum levels. Hum Genet 116, 146–151 (2005). https://doi.org/10.1007/s00439-004-1222-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-004-1222-7

Keywords

Search

Navigation