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Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin
Peter Stenvinkel1, Kai Wang, Abdul Rashid Qureshi
1Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Karolinska University Hospital, Stockholm, Sweden. peter.stenvinkel@klinvet.ki.se
Insights
Low fetuin-A levels in end-stage renal disease (ESRD) patients are linked to malnutrition, inflammation, and atherosclerosis, increasing mortality risk. Specific AHSG gene variations may accelerate vascular calcification in these patients.
Area of Science:
- Nephrology
- Cardiovascular Medicine
- Genetics
Background:
- Vascular calcification and atherosclerotic cardiovascular disease are prevalent in end-stage renal disease (ESRD) patients.
- Fetuin-A, a glycoprotein inhibiting vascular calcification, is linked to inflammation and outcomes in dialysis patients.
Purpose of the Study:
- To evaluate the association between fetuin-A, clinical phenotype, and outcomes in ESRD patients.
- To investigate the impact of fetuin gene (AHSG) polymorphisms on fetuin-A levels and patient outcomes.
Main Methods:
- A cohort of 258 ESRD patients undergoing renal replacement therapy were assessed for malnutrition, comorbidities (diabetes, CVD), carotid plaques, hs-CRP, fetuin-A, S-albumin, IL-6.
- Single nucleotide polymorphisms (SNPs) in the AHSG gene were analyzed in 215 patients.
Main Results:
- Low fetuin-A levels were independently associated with increased all-cause and cardiovascular mortality.
- Lower fetuin-A levels were observed in inflamed and malnourished ESRD patients.
- Fetuin-A was significantly associated with the presence of carotid plaques and correlated with S-albumin and IL-6.
- Patients with the AHSG 256Ser allele had lower fetuin-A and higher mortality if inflamed.
Conclusions:
- Low fetuin-A levels are linked to malnutrition, inflammation, atherosclerosis, and increased mortality in ESRD patients.
- AHSG gene variations influence circulating fetuin-A levels and patient outcomes.
- ESRD patients with the AHSG 256Ser allele may be at higher risk for accelerated vascular calcification.
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.
Conclusion:
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.