Gene polymorphisms in the heme degradation pathway and outcome of severe human sepsis


Heme and its breakdown products CO, Fe, and bilirubin are being recognized as signaling molecules or even therapeutic agents, but also exert adverse effects when released at high concentrations. Manipulating the pathway confers protection in rodent sepsis models via both control of free heme and formation of its first and higher-order products. Thus, regulatory elements present in human heme oxygenase 1 (HMOX1) and biliverdin reductases (BLVRA/B) genes might impact outcome. We tested whether a highly polymorphic (GT)n microsatellite and single-nucleotide polymorphisms in HMOX1 and BLVRA/B genes are associated with outcome of sepsis. Two cohorts (n = 430 and 398 patients) with severe sepsis were screened for single-nucleotide polymorphisms and/or the microsatellite by fragment length analysis and genotyping techniques. Heme oxygenase 1 plasma levels were determined in additional patients with severe sepsis (n = 92) by enzyme-linked immunosorbent assay. Based on mean Sepsis-related Organ Failure Assessment scores, patients homozygous for rs2071746 A allele or medium length (GT)n microsatellites of HMOX1 showed higher 28-day mortality (P = 0.047 and P = 0.033) in one cohort compared with other genotypes, whereas 90-day mortality rates showed no association. The T allele was less frequently observed in both cohorts than would be expected according to Hardy-Weinberg equilibrium. Heme oxygenase 1 plasma levels were elevated in septic patients, independent of the genotype. Single-nucleotide polymorphisms within BLVRA/B showed no association with outcome. Short (GT)n repeats that are in linkage disequilibrium with the T allele of rs2071746 in HMOX1 are associated with favorable outcome, whereas no association with gene variants of BLVRA/B, involved in the generation of higher-order metabolites, was noticed.

DOI: 10.1097/SHK.0b013e31826ae951

Projects: SepNet - German Competence Network Sepsis

Publication type: Journal article

Journal: Shock (Augusta, Ga.)

Human Diseases: Disease by infectious agent

Citation: Shock 38(5):459-465

Date Published: 2012

Registered Mode: imported from a bibtex file

Authors: Christoph Sponholz, Klaus Huse, Marcel Kramer, Evangelos J. Giamarellos-Bourboulis, Ralf A. Claus, Anna Kern, Christoph Engel, Evelyn Kuhnt, Michael Kiehntopf, Christina Routsi, Vassiliki Mylona, Iraklis Tsangaris, Stefan H. Heinemann, Konrad Reinhart, Matthias Platzer, Michael Bauer

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Sponholz, C., Huse, K., Kramer, M., Giamarellos-Bourboulis, E. J., Claus, R. A., Kern, A., Engel, C., Kuhnt, E., Kiehntopf, M., Routsi, C., Mylona, V., Tsangaris, I., Heinemann, S. H., Reinhart, K., Platzer, M., & Bauer, M. (2012). Gene Polymorphisms in the Heme Degradation Pathway and Outcome of Severe Human Sepsis. In Shock (Vol. 38, Issue 5, pp. 459–465). Ovid Technologies (Wolters Kluwer Health).

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Created: 15th Jul 2020 at 14:33

Last updated: 7th Dec 2021 at 17:58

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