title: Is fetuin-A a mortality risk factor in dialysis patients or a mere risk marker? A Mendelian randomization approach.
abstract: 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.
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. m.verduijn@lumc.nl
authors.forename: Marion
authors.initials: M
authors.lastname: Verduijn
authors.forename: Robert A
authors.initials: RA
authors.lastname: Prein
authors.forename: Peter
authors.initials: P
authors.lastname: Stenvinkel
authors.forename: Juan Jesús
authors.initials: JJ
authors.lastname: Carrero
authors.forename: Saskia
authors.initials: S
authors.lastname: le Cessie
authors.forename: Anna
authors.initials: A
authors.lastname: Witasp
authors.forename: Louise
authors.initials: L
authors.lastname: Nordfors
authors.forename: Ray T
authors.initials: RT
authors.lastname: Krediet
authors.forename: Elisabeth W
authors.initials: EW
authors.lastname: Boeschoten
authors.forename: Friedo W
authors.initials: FW
authors.lastname: Dekker
mesh_terms: D015415:Biomarkers / Q000097:blood*; D001798:Blood Proteins / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007674:Kidney Diseases / Q000628:therapy; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D006435:Renal Dialysis / Q000401:mortality*; D012307:Risk Factors; D015996:Survival Rate; D060749:alpha-2-HS-Glycoprotein
chemical_list: C556354:AHSG protein, human; D015415:Biomarkers; D001798:Blood Proteins; D060749:alpha-2-HS-Glycoprotein