Is fetuin-A a mortality risk factor in dialysis patients or a mere risk marker? A Mendelian randomization approach.
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.
Verduijn
Marion
M
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. m.verduijn@lumc.nl
Prein
Robert A
RA
Stenvinkel
Peter
P
Carrero
Juan Jesús
JJ
le Cessie
Saskia
S
Witasp
Anna
A
Nordfors
Louise
L
Krediet
Ray T
RT
Boeschoten
Elisabeth W
EW
Dekker
Friedo W
FW
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
C556354:AHSG protein, human; D015415:Biomarkers; D001798:Blood Proteins; D060749:alpha-2-HS-Glycoprotein