Journal Article

Is fetuin-A a mortality risk factor in dialysis patients or a mere risk marker? A Mendelian randomization approach

Marion Verduijn, Robert A. Prein, Peter Stenvinkel, Juan Jesús Carrero, Saskia le Cessie, Anna Witasp, Louise Nordfors, Ray T. Krediet, Elisabeth W. Boeschoten and Friedo W. Dekker

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 26, issue 1, pages 239-245
Published in print January 2011 | ISSN: 0931-0509
Published online July 2010 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfq402
Is fetuin-A a mortality risk factor in dialysis patients or a mere risk marker? A Mendelian randomization approach

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Background. Low levels of circulating fetuin-A are associated with increased mortality in dialysis patients. This study aimed to examine a potential causative role for fetuin-A on mortality by investigating whether a functional polymorphism in the alpha2-Heremans–Schmid glycoprotein (AHSG) gene associates with mortality, and by estimating the causative effect of fetuin-A levels on mortality using a Mendelian randomization design.

Methods. One thousand and forty-three incident dialysis patients were genotyped for the Thr256Ser polymorphism (rs4918) and followed up for 5 years; in 549 patients, serum fetuin-A levels were measured.

Results. Carriers of a serine allele displayed lower fetuin-A levels (−0.07 g/L per allele, P < 0.001). A small increased mortality risk was observed for the Thr/Ser and Ser/Ser genotype compared with the Thr/Thr genotype (HR 1.03, 95% CI 0.83–1.28 and HR 1.10, 95% CI 0.78–1.55, respectively). Using the AHSG genotype as an instrumental variable, the causative HR of fetuin-A levels on mortality was estimated as 1.01 per 0.1-g/L increase. Inflammation and diabetes partially modified the association of fetuin-A levels with outcome.

Conclusions. The Thr256Ser polymorphism was weakly associated with mortality, and no causative effect of fetuin-A levels on this outcome was observed. Other risk factors, including inflammation and diabetes, might lead to lower fetuin-A levels, and/or modify the effect of low fetuin-A on mortality in end-stage renal disease patients.

Keywords: alpha2-Heremans–Schmid glycoprotein; dialysis; fetuin-A; Mendelian randomization; mortality

Journal Article.  4080 words.  Illustrated.

Subjects: Nephrology

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