Erythropoietin in the general population: reference ranges and clinical, biochemical and genetic correlates

Abstract

Background: Although erythropoietin has been used for decades in the treatment of anemia, data regarding endogenous levels in the general population are scarce. Therefore, we determined erythropoietin reference ranges and its clinical, biochemical and genetic associations in the general population.

Methods: We used data from 6,777 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Fasting venous blood samples were obtained in the morning from all participants from 2001-2003. Serum erythropoietin concentrations were measured using a fully automated chemiluminescent enzyme-labeled immunometric assay. A genome-wide association study was performed to identify genetic determinants.

Results: Mean age (± SD) was 53 ± 12 years and 50% were female. Median (IQR) erythropoietin concentrations were 7.6 (5.8-9.9) IU/L in men and 7.9 (6.0-10.6) IU/L in women. A strong positive correlation was found between erythropoietin and waist circumference, glucose and systolic blood pressure (all P < 0.05). In subjects with normal renal function there was a strong exponential relation between hemoglobin and erythropoietin, whereas in renal impairment (eGFR < 60 mL/min/1.73m²) this relation was linear (men) or absent (women) (P < 0.001 for interaction). Single-nucleotide polymorphisms at the HBS1L-MYB locus were shown to be related to erythropoietin levels (P < 9x10-21), more significantly than other erythrocyte parameters.

Conclusion: We provide age-specific reference ranges for endogenous serum erythropoietin. Erythropoietin levels are positively associated with the components of the metabolic syndrome, except cholesterol. We show that even mild renal failure blunts erythropoietin production and propose the HBS1L-MYB locus as a regulator of erythropoietin.

Fig 1. Relation between hemoglobin and erythropoietin in subjects with a normal or impaired renal function.

Relation between hemoglobin and erythropoietin in men and women separated for normal (continuous line) and impaired renal function (dashed line) (eGFR ≥ or < 60 ml/min/1.73m²), the 95% confidence interval is depicted in grey.

Fig 2. Association of serum erythropoietin with single-nucleotide polymorphisms (SNP).

The -10log(P-value) is displayed on the y-axis, a higher value corresponds to a stronger association. Chromosome location is displayed on the x-axis. Each dot represents an individual SNP, the dark grey dots are the SNPs located in locus 6q23.