title: Gene polymorphisms in the heme degradation pathway and outcome of severe human sepsis.
abstract: 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.
authors.affiliation: Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sponholz
authors.forename: Klaus
authors.initials: K
authors.lastname: Huse
authors.forename: Marcel
authors.initials: M
authors.lastname: Kramer
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Claus
authors.forename: Anna
authors.initials: A
authors.lastname: Kern
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Evelyn
authors.initials: E
authors.lastname: Kuhnt
authors.forename: Michael
authors.initials: M
authors.lastname: Kiehntopf
authors.forename: Christina
authors.initials: C
authors.lastname: Routsi
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Mylona
authors.forename: Iraklis
authors.initials: I
authors.lastname: Tsangaris
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.forename: Konrad
authors.initials: K
authors.lastname: Reinhart
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D006418:Heme / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D018805:Sepsis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D012720:Severity of Illness Index; D015996:Survival Rate
chemical_list: D006418:Heme; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase