Endogenous Erythropoietin. Reference values, biochemical correlates and genetic associations in the general population; an early marker for developing heart failure?

Grote Beverborg, N. (Niels) (2014) Endogenous Erythropoietin. Reference values, biochemical correlates and genetic associations in the general population; an early marker for developing heart failure? thesis, Medicine.

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Abstract

Background: Recombinant human erythropoietin (EPO) is intensively studied as treatment for anemia and endogenous EPO as prognostic factor in heart failure patients. However, not much is known about its endogenous form in the general population, its association with individual characteristics, including cardiovascular risk factors and the relation with the risk of new onset heart failure. Objective: Our objective is to study endogenous EPO levels and its correlation with biochemical and genetic variants in the general population. Thereby, we investigate whether high EPO levels are related to an increased risk of new onset heart failure, mortality, venous thromboembolism and stroke. Methods: We used data from 6,777 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Venous blood samples were obtained in the morning from all participants from 2001-2003. Genome-wide association study was performed to identify genetic determinants of EPO levels. Results: Mean age (± SD) was 53 ± 12 years and 49.9% was female. Median (interquartile range [IQR]) EPO concentrations were 7.6 (5.8 – 9.9) IU/L in men vs. 7.9 (6.0 – 10.6) IU/L in women (p < 0.001). A strong positive correlation was found between EPO and multiple cardiovascular risk factors in both sexes, including BMI, waist circumference, glucose and blood pressure (all p < 0.05). In men and women with a normal renal function EPO increased exponentially with lowering hemoglobin levels, whereas in subjects with an impaired renal function (eGFR < 60 mL/min/1.73m²) EPO rose linear, suggesting an impaired EPO production in subjects with mildly impaired renal function (p < 0.001 for interaction). Subjects in the higher quintiles of EPO had an increased risk of new onset heart failure (p = 0.030), and EPO levels were independently associated with mortality (HR: 1.253, p = 0.033). The non-coding SNP rs7776054 and the coding SNP rs66650371, a SNP in HBS1L-MYB, are associated with EPO levels (both p < 9x10-21). Conclusions: We provide sex and age specific reference values for endogenous EPO. Erythropoietin levels are positively correlated with cardiovascular risk factors in both men and women. Even a mildly impaired renal function blunts EPO production. A locus in HBS1L-MYB is associated with EPO levels. Finally, subjects in the highest quintile of EPO have an increased risk of new onset heart failure, and EPO levels are independently associated with mortality.

Item Type:	Thesis (Thesis)
Supervisor name:	Meer, P. van der and Klip, I.T.
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:49
Last Modified:	25 Jun 2020 10:49
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/988

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