Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin.
BACKGROUND
Vascular calcification is common among end-stage renal disease (ESRD) patients and a central characteristic of the atherosclerotic cardiovascular disease observed in dialysis patients. Fetuin-A, a circulating calcium-regulatory glycoprotein that inhibits vascular calcification, is associated with inflammation and outcome in dialysis patients. In the present study, we evaluated the association between fetuin-A, clinical phenotype, and outcome, as well as the impact of fetuin gene (AHSG) polymorphisms on the protein product and outcome.


METHODS
In a cohort of 258 (161 males) ESRD patients starting renal replacement therapy [glomerular filtration rate (GFR) 6.8 +/- 0.2 mL/min] aged 52 +/- 1 years the following parameters were studied: presence of malnutrition (subjective global assessment), comorbidity [diabetes mellitus and clinical manifest cardiovascular disease (CVD)], carotid plaques (N= 101), hs-CRP, fetuin-A, S-albumin, interleukin (IL)-6, and single nucleotide polymorphisms (SNPs) in the AHSG gene (N= 215) at amino acid positions Thr248Met (C-->T), Thr256Ser (C-->G), Asp276Asn (G-->A), and Arg317Cys (C-->T).


RESULTS
Both all-cause (P < 0.001) and cardiovascular (P < 0.001) mortality were associated with low fetuin-A levels independently of age, smoking, diabetes, S-albumin, CVD, and inflammation (CRP > or =10 mg/L). Inflamed (0.199 vs. 0.247 g/L; P < 0.01) and malnourished (0.207 vs. 0.262 g/L; P < 0.05) patients had significantly lower median fetuin-A than noninflamed and well-nourished ESRD patients, respectively. In a logistic regression model (N= 101), fetuin-A was significantly (P < 0.05) associated with the presence of carotid plaques independently of age, CVD, diabetes, S-albumin, gender, and inflammation. Significant correlations were observed between fetuin-A and both S-albumin (Rho = 0.30; P < 0.0001) and IL-6 (Rho =-0.21; P < 0.01). Patients with the AHSG 256Ser allele had lower serum fetuin-A levels, and higher all-cause and cardiovascular mortality rate if they were inflamed.


CONCLUSIONS
The present study shows that a low fetuin-A level is associated with malnutrition, inflammation, and atherosclerosis (carotid plaques), as well as with increased cardiovascular and all-cause mortality. Because the present study demonstrates an effect of variations in the AHSG gene on both circulating fetuin-A levels and outcome, this indicates that ESRD patients with the AHSG 256Ser allele are at risk of accelerated vascular calcification.
Stenvinkel
Peter
P
Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Karolinska University Hospital, Stockholm, Sweden. peter.stenvinkel@klinvet.ki.se
Wang
Kai
K
Qureshi
Abdul Rashid
AR
Axelsson
Jonas
J
Pecoits-Filho
Roberto
R
Gao
Ping
P
Barany
Peter
P
Lindholm
Bengt
B
Jogestrand
Tomas
T
Heimbürger
Olof
O
Holmes
Clifford
C
Schalling
Martin
M
Nordfors
Louise
L
D001798:Blood Proteins / Q000032:analysis* / Q000235:genetics*; D002097:C-Reactive Protein / Q000032:analysis; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology* / Q000401:mortality; D002423:Cause of Death; D015331:Cohort Studies; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000150:complications / Q000401:mortality; D008297:Male; D044342:Malnutrition / Q000097:blood; D008875:Middle Aged; D011110:Polymorphism, Genetic; D060749:alpha-2-HS-Glycoprotein
C556354:AHSG protein, human; D001798:Blood Proteins; D015850:Interleukin-6; D060749:alpha-2-HS-Glycoprotein; D002097:C-Reactive Protein